WO2009140932A2 - Procédé de production de (3r,4s)-l-(4-fluorophényl)-3-[(3s)-3-(4-fluorophényl)- hydroxypropyl)] -4-(4-hydroxyphényl) -2-azétidinone - Google Patents

Procédé de production de (3r,4s)-l-(4-fluorophényl)-3-[(3s)-3-(4-fluorophényl)- hydroxypropyl)] -4-(4-hydroxyphényl) -2-azétidinone Download PDF

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WO2009140932A2
WO2009140932A2 PCT/CZ2009/000070 CZ2009000070W WO2009140932A2 WO 2009140932 A2 WO2009140932 A2 WO 2009140932A2 CZ 2009000070 W CZ2009000070 W CZ 2009000070W WO 2009140932 A2 WO2009140932 A2 WO 2009140932A2
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general formula
group
organic solvent
temperature range
inert organic
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WO2009140932A3 (fr
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Marketa Slavikova
Hana Stepankova
Josef Zezula
Josef Hajlcek
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Zentiva KS
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Zentiva KS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • 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
    • 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

Definitions

  • the invention relates to a new method of producing (3i?,45)-l-(4-fluorophenyl)-3-
  • ezetimibe is produced by addition of (iS)-4-hydroxybutanolide onto N-(4-benzyloxybenzylidene)-4-fluoroaniline by means of LDA at -78 0 C; the obtained diol is split by a periodate to the aldehyde, which reacts with 4- fluoroacetophenone O-trimethylsilylenol to form the aldol. The latter is dehydrated to form the unsaturated ketone the double bond of which, or also the benzyl protecting group, is hydrogenated on a palladium catalyst.
  • the ketone is asymmetrically reduced with a borane in the presence of a chiral ligand to form ezetimibe, or its O-benzyl derivative, which is hydrogenolyzed on a palladium catalyst.
  • Disadvantage of the process lies in necessity to work at very low temperatures and in repeated using of expensive catalysts of the palladium type.
  • ezetimibe is produced by synthesizing (S)-N- (4-methoxycarbonylbutanoyl)oxazolidide from ()S)-4-phenyl-2-oxazolidinone and glutaric acid esterchloride, followed by adding it onto said N-(4-benzyloxybenzylidene)-4-fluoroaniline in the presence of titanium(IV) chloride; the obtained product is cyclized by action of bistrimethylsilylacetamide and catalytic TBAF to an ester-azetidinone.
  • Glutaric acid methylesterchloride is produced by action of oxalylchloride on the respective acid and is reacted with (5)-4-phenyl-2- oxazolidinone to form (»S)-iV-(4-methoxycarbonylbutanoyl)oxazolidide.
  • the latter is added to said //-(4-benzyloxybenzylidene)-4-fluoroaniline in the presence of titanium(IV) chloride; the obtained product is cyclized by action of bistrimethylsilylacetamide and catalytic TBAF to the ester-azetidinone.
  • the acid obtained by alkaline hydrolysis of the ester is converted by means of oxalylchloride to the acid chloride, which reacts with a Grignard reagent in the presence of
  • the process of producing ezetimibe according to WO 2007/072088 starts from 4-(4- fluorobenzoyl)butanoic acid, which is first converted into the ethyleneketal and then reacted with (£)-4-phenyl-2-oxazolidinone to form (iS)-3-[4-[2-(4 ⁇ fluorophenyl)-[l,3] ⁇ dioxolane-2- yl]butanoyl]-4-phenyloxazolidine-2-one.
  • the process of production according to WO 2007/119106 comprises not only the above-mentioned ketal (5)-3-[4-[2-(4-fluorophenyl)-[l,3]-dioxolane-2-yl]butanoyl]-4- phenyloxazolidine-2-one but also its analogue derived from 1,3-propanediol.
  • CBS-oxazaborolidine and then deprotected by hydrogenation on Pd/C.
  • ezetimibe was also obtained by CBS reduction of the hydroxy ketone.
  • the invention provides a method of producing (3i?,4 1 S)-l-(4-fluorophenyl)-3-[(3 ⁇ S)-3-
  • PG represents a phenol protecting group such as a carbonate group, for example benzyloxycarbonyl or tert-butyloxycarbonyl groups, or an arylmethyl group, such as for instance benzyl, benzhydryl or trityl groups, or a silyl group, such as for instance tert- butyldimethylsilyl or thexyldimethylsilyl groups, with silylation agents in an inert organic solvent in the temperature range of -10 0 C to the boiling temperature of the mixture (step A); cyclizing the obtained silylether-oxazolidide of general formula III
  • PG is as defined above and X represents a silyl group of general formula SiR > lr R>2r R»3 , wherein R 1 to R 3 represent identical or different alkyl groups with 1 to 5 carbon atoms or the phenyl group, by action of &z.y(trimethylsilyl)acetamide and a base in an inert organic solvent in the temperature range of -20 to 40 0 C (step B); followed by deprotection of the obtained protected azetidinone of general formula IV
  • step C by action of deprotecting hydrogenolytic agents and/or acidic agents in an inert organic solvent (step C).
  • ezetimibe can be produced by a process starting from alcohol- oxazolidides of general formula II, which are well accessible by highly chemoselective and diastereoselective CBS reduction of the respective ketones with protected phenolic hydroxyl by means of asymmetric agents. Easily attainable high quality of these alcohols makes final chemical and optical purification of the produced substance simpler.
  • the process of producing ezetimibe of formula I from alcohol-oxazolidides of formula II consists of three steps. Step A.
  • PG represents a phenol protecting group, such as a carbonate group, for instance benzyloxycarbonyl (Cbz) or tert- butyloxycarbonyl, or an arylmethyl group, for instance benzyl, benzhydryl or trityl, or a silyl group, for instance terf-butyldimethyls
  • the silylation agents used herein include a trialkylsilylchloride of general formula ClSiR 1 R 2 R 3 , wherein R 1 to R 3 are identical or different alkyl groups with 1 to 5 carbon atoms or the phenyl group, in the amount of 1 to 2 equivalents, in the presence of a base, or hexamethyldisilazane in the presence of a catalytic amount of lithium perchlorate, preferably in the temperature range of -5 to 35 °C.
  • the trialkylsilylchloride in the presence of base is preferably trimethylsilylchloride, t ⁇ t-butyldimethylsilylchloride or thexyldimethylsilylchloride in the amount 1 to 1.6 equivalents in the presence of triethylamine or ethyldiisopropylamine, more preferably trimethylsilylchloride in the amount 1.05 to 1.4 equivalents and triethylamine in the temperature range of -5 to 25 0 C.
  • the reaction is preferably carried out at a temperature of 10 to 30 0 C.
  • the reaction is carried out in an inert organic solvent, such as, for instance, tetrahydrofuran, 2-methyltetrahydrofuran, tert- butylmethylether, toluene, dichloro ethane or dichloromethane, or their mixtures.
  • an inert organic solvent such as, for instance, tetrahydrofuran, 2-methyltetrahydrofuran, tert- butylmethylether, toluene, dichloro ethane or dichloromethane, or their mixtures.
  • Step B Cycliz.ation of silyl ethers of general formula III, wherein PG is as defined above and X is a silyl group of general formula SiR 1 R 2 R 3 , wherein R 1 to R 3 represent identical or different alkyl groups with 1 to 5 carbon atoms or the phenyl group, is carried out by action of £w(trimethylsilyi)acetamide (BSA) and a base in the amount of 0.5 to 30 %, in an inert organic solvent in the temperature range of -20 to 40 0 C.
  • BSA trimethylsilyiacetamide
  • the bases used include, for instance, a quaternary tetraalkylammonium compound such as tetrabutylammonium fluoride or tetrabutylammonium hydroxide in the amount of 0.5 - 20 molar %. Cyclization is carried out in an inert organic solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, tert- butylmethyl ether, toluene or dichloromethane, preferably in the temperature range of -15 to +35 0 C.
  • an inert organic solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, tert- butylmethyl ether, toluene or dichloromethane, preferably in the temperature range of -15 to +35 0 C.
  • cyclization is carried out by means of BSA and tetrabutylammonium hydroxide in the amount 1 to 10 %, at -15 to +5 °C.
  • cyclization is carried out by means of BSA and tetrabutylammonium fluoride in the amount of 1 to 10 %, at 15 to +25 °C.
  • Step C Deprotection of protecting groups in the compound of general formula IV, wherein PG, X and Y are as defined above, is carried out by means of deprotecting agents, such as hydrogenolytic agents, for instance, hydrogen on s catalyst, such as for instance on palladium or platinum, or acidic agents, such as mineral or organic acids, for instance hydrochloric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid or trifluoroacetic acid.
  • deprotecting agents such as hydrogenolytic agents, for instance, hydrogen on s catalyst, such as for instance on palladium or platinum
  • acidic agents such as mineral or organic acids, for instance hydrochloric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid or trifluoroacetic acid.
  • methanol, ethanol, isopropyl alcohol, 1,4-dioxane, ethyl acetate or toluene, or their mixtures are
  • hydrogen on Pd/C is used in an alcohol, such as methanol, ethanol or isopropyl alcohol, or in ethyl acetate or toluene, or their mixtures.
  • deprotection is carried out with an acid in alcohols, such as for instance with sulphuric acid, phosphoric acid, methanesulphonic acid or trifluoro acetic acid in methanol, ethanol or isopropyl alcohol, or 1,4- dioxane.
  • the obtained compound of formula I (ezetimibe) is finally purified by crystallization from a mixture of water and an alcohol, for instance 2-propanol or methanol.
  • This invention also provides a new method of producing 0,0-protected (45)-3- ⁇ (2i?,5 1 S ⁇ -5-(4-fluorophenyl)-2-[(5)-[(4-fiuorophenyl)amino](4-hydroxyphenyl)methyl]-5- hydroxypentanoyl ⁇ -4-phenyl-l,3-oxazolidine-2-ones (hereinafter "silylether-oxazolidides”) of general formula III
  • PG represents a phenol protecting group, such as a carbonate group, for instance benzyloxycarbonyl or tert-butyloxycarbonyl, or an arylmethyl group, for instance benzyl, benzhydryl or trityl, or a silyl group, for instance fert-butyldimethylsilyl or thexyldimethylsilyl
  • X is a silyl group of general formula SiR 1 R 2 R 3 , wherein R 1 to R 3 are identical or different alkyl groups with 1 to 5 carbon atoms or the phenyl group, which comprises reducing a ketone-oxazolidide of general formula V
  • PG is defined as above, with asymmetrical borane agents in an inert organic solvent in the temperature range of -30 to
  • PG is defined as above, by means of a silylation agent in an inert organic solvent in the temperature range of -10 °C to the boiling temperature of the mixture (step T).
  • Step 1 Reduction of ketones of general formula V with protected phenolic hydroxyl is carried out using an asymmetrical borane agent consisting of a source of borane and a chiral ligand.
  • the sources of borane that can be used include a complex of borane, for instance with dimethylsulphide, tetrahydrofuran, dimethylaniline or diethylaniline, and the chiral ligands that can be used include a 2-substituted (i?)-CBS-oxazaborolidine, such as for example (i?)-2- methyl-CBS-oxazaborolidine, (i?)-2-methoxy-CBS-oxazaborolidine or (i?)-2-(o-tolyl)-CBS- oxazaborolidine in the amount of 1 to 100 mol %, preferably 1 to 25 mol %; more preferred is using of 4 to 10 % of the chiral ligand.
  • Reduction can be preferably carried out in the presence of a catalytic amount of protic or Lewis acids, such as methanesulphonic, j?-toluenesulphonic, trifluoroacetic acids or borotrifluoride etherate.
  • protic or Lewis acids such as methanesulphonic, j?-toluenesulphonic, trifluoroacetic acids or borotrifluoride etherate.
  • Suitable protecting groups PG include a carbonate group, such as for instance benzyloxycarbonyl or ter?-butyloxycarbonyl, or an arylmethyl group, such as for instance benzyl, benzhydryl or trityl, or a silyl group, such as for instance tert-butyldimethylsilyl or thexyldimethylsilyl.
  • Suitable inert organic solvents are, for instance, tetrahydrofuran, 2- methyltetrahydrofuran, tert-butylmethylether, toluene or dichloromethane, or their mixtures.
  • PG is a phenol protecting group, such as a carbonate group, such as for instance benzyloxycarbonyl or tert- butyloxycarbonyl, or an arylmethyl group, such as for instance benzyl, benzhydryl or trityl, or a silyl group, such as for instance tert-butyldimethyl
  • silylation agents that can be used include trialkylsilylchloride of general formula ClSiR 1 R 2 R 3 , wherein R 1 to R 3 are identical or different alkyl groups with 1 to 5 carbon atoms or the phenyl group, in the presence of a base, such as for instance trimethylsilylchloride, tert-butyldimethylsilylchloride or thexyldimethylsilylchloride in the presence of triethylamine or ethyldiisopropylamine, or hexamethyldisilazane in the presence of a catalytic amount of lithium perchlorate, preferably in the temperature range of -5 to 35 °C.
  • a base such as for instance trimethylsilylchloride, tert-butyldimethylsilylchloride or thexyldimethylsilylchloride in the presence of triethylamine or ethyldiisopropyl
  • the trialkylsilylchlorides in the presence of bases preferably include trimethylsilylchloride, tert-butyldimethylsilylchloride or thexyldimethylsilylchloride in the amount of 1 to 1.6 equivalents in the presence of triethylamine or ethyldiisopropylamine, more preferably trimethylsilylchloride in the amount of 1.05 to 1.4 equivalents and triethylamine in the temperature range of -5 to 25 °C.
  • the reaction is preferably carried out at temperature of 10 to 30 °C.
  • reaction is carried out in an inert organic solvent, such as, for instance, tetrahydrofuran, 2-methyltetrahydrofuran, tert- butylmethylether, toluene or dichloromethane, or their mixtures.
  • inert organic solvent such as, for instance, tetrahydrofuran, 2-methyltetrahydrofuran, tert- butylmethylether, toluene or dichloromethane, or their mixtures.
  • reaction mixture is stirred at a temperature of -5 to -10 0 C for 2 h, progress of the reaction being monitored by TLC (silica gel; eluent PE : ethyl acetate 7 : 3).
  • TLC sica gel; eluent PE : ethyl acetate 7 : 3
  • the reaction is terminated by addition of 4.2 ml of acetic acid.
  • the solution is taken out from the cooling bath, left to temper at about 0 0 C, and diluted with 120 ml of dichloromethane and 45 ml of water.
  • the organic portion is separated and evaporated in a rotary vacuum evaporator to dryness (temperature of the bath up to 45 °C).
  • the evaporation residue is poured over with 50 ml of methanol and evaporated once again in order to remove residues of dichloromethane. An oily evaporation residue is obtained, which is used for deprotection without purification.
  • the obtained oil is dissolved in 150 ml of methanol, 3 % Pd/C (0.66 g, . 50 % of water) is added, and the mixture is hydrogenated at atmospheric pressure for 18 h. Then, completeness of hydrogenation is checked by means of TLC (silica gel; eluent PE : ethyl acetate 1 : 1). The catalyst is filtered and washed with methanol (Seitz filter). The filtrate is concentrated in a rotary vacuum evaporator to the volume of 70 ml (or is diluted to this volume); bath temperature up to 45 °C. The concentrated filtrate is mixed with 35 ml of water under stirring at room temperature and the turbid solution is seeded with ezetimibe.
  • the formed ezetimibe starts crystallizing and the mixture is stirred at room temperature for 1 h.
  • the eliminated product is sucked off on sintered glass and washed with 12 ml of a mixture methanol : water (2:1).
  • the obtained product is dried in the air at room temperature.
  • the mixture is left to heat under stirring from 0 °C to the laboratory temperature during 1 h, progress of the reaction being monitored by TLC (silica gel; eluent hexane : ethyl acetate 8 : 3).
  • TLC sica gel; eluent hexane : ethyl acetate 8 : 3.
  • the reaction mixture is diluted with ethyl acetate (25 ml), washed with an aqueous solution of NaHCO 3 (Ix) and with water (Ix); and after drying (Na 2 SO 4 ), it is evaporated in a rotary vacuum evaporator.
  • the oily evaporation residue is purified by chromatography on silica gel (eluent hexane : ethyl acetate 7 : 3).
  • reaction mixture is stirred at a temperature of 0 - 10 0 C for 2.5 h, the reaction process being monitored by means of TLC (silica gel; eluent petrol ether : ethyl acetate 1 : 1).
  • TLC sica gel; eluent petrol ether : ethyl acetate 1 : 1).
  • water (20 ml) is added at laboratory temperature, the reaction vessel is rinsed with dichloromethane (20 ml).
  • the separated organic phase and the rinsed portion are combined, washed with brine (20 ml), and dried with sodium sulphate.
  • a crystalline residue (6.44 g) is obtained by concentrating the organic phase in a vacuum evaporator, which is dissolved in boiling ethyl acetate (35 ml).
  • reaction mixture foams and releases hydrogen and dimethylsulphide.
  • the reaction mixture is stirred at room temperature for additional 15 min; then, it is diluted with 10 ml of 1 N HCl and stirred for additional 15 min; foam is again formed and gases released.
  • reaction mixture is stirred for additional 45 min, progress of reduction being monitored by means of TLC (silica gel; eluent petrol ether : ethyl acetate 1 : 1). After the starting substance has disappeared, the reaction is terminated by 0 careful dropwise addition of 50 ml of methanol. During decomposition, the reaction mixture foams and releases hydrogen and dimethylsulphide. After adding methanol, the reaction mixture is stirred at room temperature for additional 0.5 h and then it is diluted with 120 ml of 1 N HCl; the mixture again foams and releases gases.
  • the reaction mixture is diluted with 250 ml of dichloromethane, the organic portion is separated and dried with anhydrous sodium sulphate.
  • the extract is concentrated in a rotary vacuum evaporator to dryness (temperature of bath 40 - 45 0 C).
  • the crystalline evaporation residue (18.82 g) is crystallized from the mixture of ethyl acetate and methanol: the evaporation residue is mixed in 250 ml of methanol and the obtained suspension is heated under reflux. Ethyl acetate is slowly added to the boiling suspension until a solution is formed
  • a 1 M solution of titanium(IV) chloride in CH 2 Cl 2 (29.5 ml, 29.5 mmol; 0.94 eq.) and titanium(IV) isopropoxide (2.95 ml, 9.9 mmol; 0.32 eq.) is gradually added to 50 ml of dry CH 2 Cl 2 under stirring at temperature 0 - 5 0 C. The solution is stirred under cooling for 1 h.
  • a suspension of iV-(4-hydroxybenzylidene)-4-fluoroaniline (8.44 g; 39.2mmol; 1.25 eq.) in dichloromethane (70 ml) is cooled under stirring to 0 °C and a 50 % toluene solution of benzyl chloroformate (13.8 ml, 41.4 mmol; 1.3 eq.) is added. Then diisopropylethylamine (21.5 ml, 125.6 mmol, 4.02 eq.) is added at temperature 0 to 5 °C (slightly exothermic) within 10 min, wherein the suspension changes to a solution.
  • reaction mixture is left to warm up spontaneously to laboratory temperature (about 1.5 h), and then cooling is started again.
  • a temperature of about -5 °C a solution of (5)-3-[5,5-dimethoxy-5-(4-fluorophenyl)-l- oxopentyl]-4-phenyloxazolidin-2-one (12.55 g, 31.26 mmol) in 50 ml Of CH 2 Cl 2 is added and the mixture is cooled down to the temperature -35 0 C under stirring (about 20 min).
  • a solution of the titanium agent (corresponding to 1.26 eq.
  • TiCl 3 (Oz-Pr) is added dropwise in such a way that the temperature does not exceed -30 0 C (about 20 min).
  • the reaction mixture is getting dark, stirred at the temperature -35 °C for 3 h and then terminated by addition of acetic acid (8.4 ml, 147 mmol), which is added dropwise under cooling during 5 - 10 min. After additional 10 min, cooling of the reaction mixture is stopped, 0.46 M citrate buffer (180 ml) is added and the two-phase mixture is stirred for at least 3 h (possibly also overnight), wherein it is left to warm up slowly to laboratory temperature.
  • the water phase is separated and shaken with 100 ml of CH 2 Cl 2 .
  • the combined organic portions are washed with 100 ml of water and evaporated in a rotary vacuum evaporator at the bath temperature 40 0 C.
  • 75 ml of ethyl acetate and 75 ml of methanol are added to the evaporation residue and the thick suspension is boiled under reflux for 1 h and then stirred at laboratory temperature for 2 h.
  • the eliminated crystals are sucked off and washed with 30 ml of a mixture methanol ethyl acetate (1 : 1). Melting temperature 178 — 179.5 °C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne un procédé de production de (3R,4S)-l-(4-fluorophényl)-3-[(3S)-3- (4-fluorophényl)-3-hydroxypropyl)]-4-(4-hydroxyphényl)-2-azétidinone (ézétimibe) représenté par la formule (I). On commence par une silylation d'oxazolidide-alcool représenté par la formule (II) dans laquelle PG est un groupe protégeant le phénol, notamment un groupe carbonate tel que benzyl-oxycarbonyle ou tert-butyl-oxycarbonyle, ou un groupe aryl-méthyle tel que benzyle, benzhydryle ou trityle, ou encore un groupe silyle tel que tert-butyl-diméthylsilyle ou thexyl-diméthylsilyle, la silylation étant réalisée par des agents de silylation dans un solvant organique inerte dans une plage de températures allant de -10°C à la température d'ébullition du mélange. On réalise ensuite une cyclisation du silyléther-oxazolidide obtenu représenté par la formule générale (III) dans laquelle PG est tel que précédemment décrit et X est un groupe silyle représenté par la formule SiR1R2R3 dans laquelle R1 à R3 sont des groupes C1-C5 alkyle identiques ou différents ou le groupe phényle, la cyclisation résultant de l'action de bis(triméthylsilyl)acétamide et d'une base dans un solvant organique inerte dans une plage de températures allant de-20°C à 40°C. Enfin, on réalise une déprotection de l'azétidinone protégé résultant représenté par la formule (IV) dans laquelle PG est tel que précédemment décrit, et Y est hydrogène ou le groupe X défini ci-dessus, la déprotection résultant de l'action d'hydrogénolytiques déprotecteurs et/ou d'agents acides dans un solvant inorganique inerte.
PCT/CZ2009/000070 2008-05-21 2009-05-15 Procédé de production de (3r,4s)-l-(4-fluorophényl)-3-[(3s)-3-(4-fluorophényl)- hydroxypropyl)] -4-(4-hydroxyphényl) -2-azétidinone Ceased WO2009140932A2 (fr)

Applications Claiming Priority (2)

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CZ20080317A CZ2008317A3 (cs) 2008-05-21 2008-05-21 Zpusob výroby (3R,4S)-1-(4-fluorfenyl)-3-[(3S)-3-(4-fluorfenyl)-3-hydroxypropyl)]-4-(4-hydroxyfenyl)-2-azetidinonu
CZPV2008-317 2008-05-21

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WO2009140932A2 true WO2009140932A2 (fr) 2009-11-26
WO2009140932A3 WO2009140932A3 (fr) 2010-01-14

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Cited By (8)

* Cited by examiner, † Cited by third party
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CN101845010A (zh) * 2010-02-10 2010-09-29 浙江大学 一种制备伊替米贝的方法
ES2372460A1 (es) * 2010-07-09 2012-01-20 Moehs Ibérica S.L. Nuevo método para la preparación de ezetimiba.
US8178665B2 (en) * 2005-12-20 2012-05-15 Richter Gedeon Nyrt. Process for the production of ezetimibe and intermediates used in this process
CN102850390A (zh) * 2011-07-01 2013-01-02 江苏豪森药业股份有限公司 依折麦布的中间体及其制备方法
US20130040927A1 (en) * 2011-02-16 2013-02-14 Pivotal Therapeutics Inc. Cholesterol absorption inhibitor and omega 3 fatty acids for the reduction of cholesterol and for the prevention or reduction of cardiovascular, cardiac and vascular events
CN103864708A (zh) * 2012-12-12 2014-06-18 天津市医药集团技术发展有限公司 一种依折麦布中间体的制备方法
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CN105985275A (zh) * 2015-02-15 2016-10-05 和鼎（南京）医药技术有限公司 一种依泽替米贝及其中间体的制备方法

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US9388440B2 (en) 2009-04-01 2016-07-12 Mylan Laboratories Limited Enzymatic process for the preparation of (S)-5-(4-fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one, an intermediate of Ezetimibe and further conversion to Ezetimibe
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US20130040927A1 (en) * 2011-02-16 2013-02-14 Pivotal Therapeutics Inc. Cholesterol absorption inhibitor and omega 3 fatty acids for the reduction of cholesterol and for the prevention or reduction of cardiovascular, cardiac and vascular events
US8952000B2 (en) * 2011-02-16 2015-02-10 Pivotal Therapeutics Inc. Cholesterol absorption inhibitor and omega 3 fatty acids for the reduction of cholesterol and for the prevention or reduction of cardiovascular, cardiac and vascular events
CN102850390A (zh) * 2011-07-01 2013-01-02 江苏豪森药业股份有限公司 依折麦布的中间体及其制备方法
CN103864708A (zh) * 2012-12-12 2014-06-18 天津市医药集团技术发展有限公司 一种依折麦布中间体的制备方法
CN105985275A (zh) * 2015-02-15 2016-10-05 和鼎（南京）医药技术有限公司 一种依泽替米贝及其中间体的制备方法
CN105985275B (zh) * 2015-02-15 2018-12-14 和鼎（南京）医药技术有限公司 一种依泽替米贝及其中间体的制备方法

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