WO2008096372A2 - Procédé de préparation de l'ézétimibe extrêmement pur au moyen de nouveaux intermédiaires - Google Patents

Procédé de préparation de l'ézétimibe extrêmement pur au moyen de nouveaux intermédiaires Download PDF

Info

Publication number
WO2008096372A2
WO2008096372A2 PCT/IN2008/000072 IN2008000072W WO2008096372A2 WO 2008096372 A2 WO2008096372 A2 WO 2008096372A2 IN 2008000072 W IN2008000072 W IN 2008000072W WO 2008096372 A2 WO2008096372 A2 WO 2008096372A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
phenyl
oxo
benzyloxy
ezetimibe
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2008/000072
Other languages
English (en)
Other versions
WO2008096372A3 (fr
Inventor
Chidambaram Venkateswaran Srinivasan
Rahul Saxena
Pranav Gupta
Lalit Wadhwa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
IND-SWIFT LABORATORIES Ltd
Ind Swift Laboratories Ltd
Original Assignee
IND-SWIFT LABORATORIES Ltd
Ind Swift Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by IND-SWIFT LABORATORIES Ltd, Ind Swift Laboratories Ltd filed Critical IND-SWIFT LABORATORIES Ltd
Publication of WO2008096372A2 publication Critical patent/WO2008096372A2/fr
Anticipated expiration legal-status Critical
Publication of WO2008096372A3 publication Critical patent/WO2008096372A3/fr
Ceased legal-status Critical Current

Links

Classifications

    • 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

Definitions

  • the present invention provides an industrially advantageous process for the preparation of ezetimibe of formula I, using novel intermediates.
  • the present invention further relates to a purification process for preparing enantiomerically and chemically pure ezetimibe which is substantially free of impurities.
  • Ezetimibe of Formula-I is indicated as monotherapy for the treatment of primary hypercholesterolemia and homozygous sitosterolemia and is chemically known as l-(4- fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2- azetidinone.
  • Ezetimibe was first disclosed in US Patent 5,767,115 (RE 37,721) as a useful hypocholesterolemic agent in the treatment and prevention of artherosclerosis.
  • the process comprises reacting (S)-4-phenyl-2-oxazolidinone with methyl-4-(chloroformyl) butyrate to obtain an ester of formula,
  • PCT application WO 2006/137080 discloses a process for the preparation of ezetimibe, wherein the coupling reaction between acid chloride and p-fluorophenyl zinc chloride is carried out in the presence of palladium acetate.
  • ezetimibe can contain extraneous compounds or impurities. These impurities may be, for example, starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in ezetimibe, or any active pharmaceutical ingredient ("API"), are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. At certain stages during processing of an
  • API such as ezetimibe
  • HPLC high performance liquid chromatography
  • TLC thin-layer chromatography
  • Prior art processes disclose several processes for the preparation of pure ezetimibe using crystallization with solvents like methanol, methyl tertiary-butyl ether, isopropyl alcohol, etc.
  • the present invention is thus directed to an industrially advantageous process for the preparation of ezetimibe which improves the economics by employing less expensive and less hazardous raw materials and is more productive. Further the present invention provides a process for the purification of ezetimibe to provide ezetimibe having improved chemical and/or enantiomeric purity.
  • the present invention provides a novel and alternative process for the preparation of l-(4- fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxy ⁇ ropyl]-4(S)-(4-hydroxyphenyl)-2- azetidinone herein referred to as ezetimibe of formula I,
  • Formula-I comprising: a) reacting pentanedioic acid monobenzyl ester of formula II,
  • Formula-IV in the presence of lewis acid like titanium tetrachloride along with titanium isopropoxide in a suitable organic solvent to form 4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5- oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)pentanoic acid benzyl ester of formula V,
  • Another aspect of the present invention provides novel intermediates and processes useful for the preparation of ezetimibe.
  • the present invention provides a process for the purification of ezetimibe, comprising a) dissolving ezetimibe in a suitable solvent specifically tertiary butanol, b) admixing an anti-solvent specifically water with cooling to obtain a precipitate, c) filtering the product, d) optionally repeating the steps a-c, and subsequently e) isolating the highly pure ezetimibe therefrom.
  • Another embodiment of the present invention provides a process for purification of ezetimibe, comprising a) providing a solution of ezetimibe in a suitable solvent specifically aqueous tertiary butanol at reflux, b) cooling thexeaction mass to obtain a precipitate, c) filtering the product, d) optionally repeating the steps a-c, and subsequently e) isolating the highly pure ezetimibe therefrom.
  • R is selected from H or benzyl
  • the present invention provides novel intermediates and novel process for the preparation of l-(4- fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2- azetidinone (Ezetimibe) of formula I,
  • Formula-Ill a novel and key intermediate for the preparation of ezetimibe and further forms a part of the present invention.
  • the starting materials can be procured from the market or can be prepared according to the process of the present invention disclosed further in this invention or by methods disclosed in any of the known processes.
  • an inert organic solvent selected from halogenated solvents preferably dichloromethane, is added to the pentanedioic acid monobenzyl ester of formula II and the reaction mass is allowed to cool to a temperature of about 10-20 0 C.
  • a suitable base or acid trapping agent is added and the reaction mass is stirred for a period of about 5-20 minutes under inert atmosphere.
  • Suitable base can be selected from tertiary amine such as diisopropyl ethylamine, tributylaniine, triethylamine. Preferably triethylamine is used.
  • pivaloyl chloride is added slowly while maintaining the reaction temperature between 10-35 0 C.
  • reaction mass sulfuric acid solution is added while stirring the reaction mass for a period of about 10-30 minutes.
  • the organic layer is separated and the solvent is distilled off fully under vacuum.
  • alcoholic solvent is added followed by stirring at ambient temperature for 15 minutes.
  • the reaction mixture may be slowly cooled, filtered, washed with alcoholic solvent and dried at 40 0 C under vacuum to obtain 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester of formula III in high yield and having purity greater than 98% by high performance liquid chromatography.
  • pentanedioic acid monobenzyl ester of formula II as given above.
  • pentanedioic acid monobenzyl ester can be prepared from glutaric acid. More particularly, glutaric acid along with benzyl alcohol, p-toluene sulfonic acid and suitable solvent are added together and the reaction mass is heated to a reflux temperature. Suitable solvent can be selected from aromatic hydrocarbons, halogenated solvents. Preferably toluene is used. The reaction is further checked for completion by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) for the absence of benzyl alcohol.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • reaction mass After completion of reaction, the reaction mass is cooled to ambient temperature, followed by the addition of demineralized water. The reaction mass is further stirred for a few minutes. The organic layer is separated and the solvent is distilled off completely under vacuum to get pentanedioic acid monobenzyl ester of formula II as oil.
  • reaction mass is cooled to 0-5 0 C and the solid is filtered, washed with hexane and finally dried under vacuum at 50-55 0 C to get 4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5- oxo-5-(2-oxo-4-phenyl-oxazolidine-3-yl)pentanoic acid benzyl ester of formula V having purity greater than 99% by high performance liquid chromatography.
  • Benzylated schiff base can be procured from the market or can be prepared according to the process of the present invention disclosed further in this invention or by methods disclosed in any of the known processes.
  • Alcoholic solvent preferably ethanol is added to the reaction mass and is heated to reflux temperature to get a clear solution.
  • the reaction mass is then cooled to ambient temperature slowly and stirred for 2-4 hours.
  • the reaction mass is then preferably cooled to 0 0 C and stirred at a temperature of below 5°C for few hours.
  • a suitable base is added to a solution of 3-[2-(4-benzyloxy-phenyl)-l-(4- fluorophenyl)-4-oxo-azetidin-3-yl]- ⁇ ropionic acid benzyl ester of formula VI in a suitable solvent at ambient temperature with continuous stirring.
  • Suitable base is selected from alkali metal hydroxides, alkali metal carbonates/ bicarbonates. Preferably lithium hydroxide is used.
  • Solvent can be selected from tetrahydrofuran, methanol, ethanol, isopropyl alcohol, acetone and methyl isobutyl ketone.
  • the reaction completion can be checked by thin layer chromatography or high performance liquid chromatography for the absence of starting material.
  • ezetimibe is prepared by reacting 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4- oxo-azetidin-3-yl] -propionic acid of formula VII or its reactive derivative with Grignard reagent in the presence of iron catalyst in suitable solvent and the resulting compound is converted to ezetimibe by performing hydrogenation and debenzylation or vice versa.
  • Catalyst can be selected from iron catalysts such as iron acetyl acetonate, iron chloride and the like.
  • a freshly prepared Grignard solution is added slowly at same temperature and the reaction mass is stirred further for few minutes to few hours.
  • Grignard solution can be prepared by using magnesium turnings, 4- bromofluoro benzene and tetrahydrofuran, optionally with catalytic amount of iodine.
  • the reaction completion can be checked by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) for the presence of starting material to be not more than 1%.
  • 4-(4-Benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2- one of formula IX can further be converted to ezetimibe by the methods well known in art by main two processes. In one aspect, it is reduced to 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)- 3-[3[(4-fluoro-phenyl)-3-hydoxy-propyl]-azetidin-2-one of formula X and then debenzylated to form ezetimibe.
  • 4-(4-berizyloxy-phenyl)-l-(4-fluoro-phenyl)-3- [3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one is debenzylated to form 4-(4-hydroxy- phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one and further reduced to form ezetimibe.
  • 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fiuoro-phenyl)-3-oxo- propyl]-azetidin-2-one of formula EX is reduced to 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)- 3-[3[(4-fluoro-phenyl)-3-hydoxy-propyl]-azetidin-2-one of formula X and then debenzylated to form ezetimibe.
  • compound of formula IX in a suitable anhydrous organic solvent is added slowly to a mixture of suitable reducing agent and a suitable chiral promoter/catalyst in catalytic or stoichiometric amount at a temperature of below 5 0 C under inert atmosphere.
  • suitable anhydrous organic solvent can be selected from dichloromethane, tetrahydrofuran, toluene, xylene and the like.
  • Reducing agent can be selected from borane dimethyl sulfide complex, sodium borohydride, a substituted borohydride eg.[ cbz-Proline] 3 BHNa and the like, while the chiral promoter/catalyst can be selected from (i?)-2-methyl-CBS-oxazaborolidine, R- butyl CBS, i?-phenyl CBS.
  • the reaction completion can be checked by thin layer chromatography or high performance liquid chromatography for the presence of starting material to be not more than 0.5%.
  • Compound of formula X can further be debenzylated to ezetimibe of formula I using conventional techniques known in the art or by the method described herein.
  • Compound of formula X is dissolved in suitable alcoholic solvent like C 1 -C 4 alcohols and a hydrogenation catalyst is added.
  • Hydrogenation catalyst can be selected from Palladium carbon. More preferably 10% by weight palladium on carbon is used. Reactions that use a palladium reagent to affect the conversion of a compound of formula X to ezetimibe should be conducted in the presence of an additional compound capable of acting as a reductant, such as hydrogen.
  • Non-precious metal catalysts especially those based on nickel such as Raney nickel and "Urushibara nickel can also be employed. More preferably 10% by weight palladium supported on carbon is used. Reaction is conducted preferably in the presence of an additional compound, such as hydrogen. The reaction mixture is exposed to hydrogen gas under a pressure of 4.00-5.50 kg/cm 2 at a temperature of about 25-45°C till the reaction goes to completion. The catalyst is filtered through hyflo bed and product is extracted after work up with organic solvent like toluene.
  • the product is found to contain 4,4'-difluoro-biphenyl as impurity which can be removed by treating the product with a suitable solvent like n-heptane at a temperature of 70-100 0 C and then cooling to 10-25 0 C.
  • the impurity is isolated preferably by decantation. This process can be repeated several times, preferably till the thin layer chromatography (TLC) shows the absence of biphenyl impurity.
  • TLC thin layer chromatography
  • the product can further optionally be purified of the undesired impurities by dissolving the product in suitable solvent like chloroform and passing it through a column packed with silica gel in chloroform. The column is then washed with chloroform.
  • the eluted chloroform is distilled out at 50-55 0 C to obtain pure 4-(4-hydroxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro- phenyl)-3-oxo-propyl]-azetidin-2-one.
  • Suitable organic solvent can be selected from dichloromethane, tetrahydrofuran, toluene, xylene and the like.
  • Reducing agent can be selected from borane dimethylsulfide complex, sodium borohydride, a substituted borohydride eg.[ cbz-Proline] 3 BHNa and the like, while the chiral promoter/catalyst can be selected from (i?)-2-methyl-CBS-oxazaborolidine, (i?)-butyl CBS, (2?)-phenyl CBS.
  • the reaction completion can be checked by thin layer chromatography or high performance liquid chromatography for the presence of starting material to be not more than 1.0%, preferably not more than 0.5%. Addition of hydrogen peroxide to affect the decomposition of borane complex followed by extraction with suitable organic solvent like dichloromethane gives crude ezetimibe.
  • One another embodiment of the present invention relates to a process for the synthesis of highly pure exetimibe by crystallizing crude ezetimibe so obtained by the processes of the present invention.
  • the term 'crude ezetimibe' refers to ezetimibe containing more than about 1.0 percent area by HPLC of the 'bis impurity' and 'keto impurity' along with certain other known impurities; and more than about 1.0 percent area by HPLC of the '(3R) isomer impurity.'
  • the term "chemically pure ezetimibe” refers to ezetimibe, containing less than about 0.15 percent area by HPLC of the 'bis impurity', 'keto impurity' and other unidentified impurities.
  • the level of these impurities is less than about 0.10 percent area by HPLC, and, most preferably, less than about 0.07 percent area by HPLC.
  • a chemically pure ezetimibe in accordance with the invention may be substantially free of these impurities, such that the level of
  • enantiomerically pure ezetimibe refers to ezetimibe, containing less than about 0.15 percent area by HPLC of the '(3R) isomer impurity'.
  • the level of the ezetimibe containing less than about 0.15 percent area by HPLC of the '(3R) isomer impurity'.
  • '(3R) isomer impurity' is less than about 0.10 percent area by HPLC.
  • the chemical purity of ezetimibe in the present invention relates to the level of two impurities in the final product.
  • impurities include:
  • R is selected from H or benzyl
  • the bis impurity forms the inventive part of the present invention and contaminates ezetimibe of formula I.
  • 'Bis impurity' is typically obtained during the synthesis of 4-(4-benzyloxy-phenyl)-l-(4-fluoro- ⁇ henyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one and is exceptionally difficult to remove from both the said intermediate and the crude ezetimibe obtained therefrom.
  • 'Keto impurity' is an intermediate, which may remain unreacted during the reduction step with borane dimethyl sulfide complex and get carry forward to final product as an impurity.
  • the enantiomeric purity in the present invention relates to the level of the (3R,4S)-l-(4-fluoro- phenyl)-3-[(3R)-3-(4-fluoro-phenyl)-3-hydroxy-propyl]-4-(4-hydroxy-phenyl)-azetidin-2-one, referred herein as '(3R) isomer impurity' of following formula .
  • the progress of the purification process and the presence or absence of impurities can be monitored using HPLC analysis.
  • One embodiment of the present invention provides a process for the purification of crude ezetimibe comprising heating a mixture of crude ezetimibe and an alcoholic solvent, specifically tertiary-butanol to a temperature of between about 70°C and above up to the reflux temperature of the solvent, and cooling the solution to a temperature of about 40°C to about 60°C.
  • the process further includes combining the solution with an anti solvent that is a poor solvent for ezetimibe and which when mixed with a solution of ezetimibe, causes it to precipitate.
  • the anti solvent is water.
  • the reaction mass is further cooled to 0-5 0 C and maintained for a time sufficient to precipitate ezetimibe in high purity.
  • the precipitated product can be isolated by the methods well known in the art like filtration, decantation, centrifugation and the like. Typically, this product is isolated by filtration.
  • Another embodiment of the present invention provides a process for the purification of ezetimibe by providing a solution of crude ezetimibe in a suitable solvent specifically aqueous tertiary butanol at reflux. This is followed by cooling the reaction mass initially to room temperature and finally at 0 to 5°C to induce precipitation and isolation of ezetimibe from the reaction mixture.
  • the product can be isolated by any standard method known in the art such as by filtration, centrifugation or decantation. Typically, this product is isolated by filtration.
  • the ezetimibe obtained after the crystallization is chemically and enantiomerically purer than the crude ezetimibe used as the starting material.
  • the obtained ezetimibe contains a lower level of the 'keto' and 'bis' impurity and a lower level of the '(3R) isomer impurity'.
  • the crystallization process may be repeated in order to increase the purification even further either with the same or a different solvent that was used for the first crystallization.
  • Coupling reaction is carried out in the presence of cheap iron catalyst without using highly hygroscopic zinc chloride derivative, toxic and expensive tetrakis(triphenyl phosphonium) palladium, palladium acetate as reported in prior art.
  • Example 3 Preparation of Benzylated Schiff Base p-Hydroxy benzaldehyde (100 g) was taken along with demineralized water (1.0 L), sodium hydroxide (34.40 g) and stirred at ambient temperature for 5 minutes. Dichloromethane (750 ml) and tetrabutylammonium bromide (26.40 g) were added and stirred for 10 minutes. Benzyl bromide (107 ml) was added and then the reaction mass was stirred at 25-3O 0 C for 90 minutes. The two layers were separated. Aqueous layer was extracted with dichloromethane (200 ml) and the extraction was added to the main organic layer.
  • Dichloromethane (1.532 L) was cooled to O 0 C under nitrogen atmosphere. Titanium tetrachloride (37.53 ml) and Titanium isopropoxide (32.40 ml) were added and the reaction mass was stirred at 0 to -5°C for 15 minutes. A solution of 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester (125 g) in methylene chloride (375 ml) was added slowly at 0 to -5°C. The reaction mass was stirred at 0 to -5°C for 30 minutes.
  • Diisopropylethylamine (166.8 ml) was added dropwise at O to -5 0 C and then the reaction mass was stirred at 0 to -5 0 C for 60 minutes.
  • the reaction mass was cooled to -25°C and benzylated schiff base (115 g) was added.
  • the reaction mass was maintained at -15 to -2O 0 C for 6 hours.
  • After 6 hours the reaction mass was cooled to -3O 0 C and then a solution of acetic acid (100 ml) and dichloromethane (100 ml) was added slowly at -30 to -25 0 C.
  • the reaction mass was poured into 7% aqueous tartaric acid solution (1.75 L) precooled to 0 0 C.
  • reaction mass was raised to 25°C and then maintained for 30 minutes. 20% aqueous sodium bisulfite solution (625.50 ml) was added and then the reaction mass was stirred at 25-3O 0 C for 30 minutes. The two layers were separated. Aqueous layer was extracted with dichloromethane (250 ml) and added to the main organic layer. The combined organic layer was washed with demineralized water (2x800 ml). Solvent was removed by distillation at atmospheric pressure and finally degassed under ⁇ -vacuum. Ethyl acetate (375 ml) was added and the reaction mass was heated to reflux temperature to get a clear solution.
  • reaction mass was cooled to 6O 0 C and then hexane (750 ml) was added slowly.
  • the reaction mass was cooled to ambient temperature and maintained for 2 hours.
  • the reaction mass was cooled to 0-5 0 C and maintained at this temperature for 2 hours.
  • the solid was filtered and washed with hexane (250 ml). Finally the solid was dried under vacuum at 50-55 0 C to get 186 g of the title compound having purity of 99.48 % by HPLC.
  • reaction mass was maintained at 38-42°C and reaction completion was checked by HPLC. Thereafter the reaction mass was cooled to ambient temperature and IN hydrochloric acid solution (1.86 L) was added. The reaction mass was stirred for 15 minutes. The two layers were separated. Organic layer was washed with 10% aqueous sodium bicarbonate solution (1.86 L) and 25% brine (1.86 L) respectively. The organic layer was dried over sodium sulfate. Silica gel (55.8 g) and activated carbon (37.20 g) were added and the reaction mass was stirred at ambient temperature for 30 minutes. The reaction mass was filtered through hyflo and the hyflo bed was washed with methyl tertiarybutyl ether (186 ml).
  • Tetrahydrofuran 150 ml was added to the same and the reaction mass was cooled to -78°C under nitrogen. Iron acetyl acetonate (0.84 g) was added and the reaction mass was further stirred at -78 to -85°C for 5 minutes. A freshly prepared Grignard solution (prepared by using 2.86 g magnesium turnings, 20.82 g 4-bromofluoro benzene and 100 ml tetrahydrofuran) was added dropwise at -78 to -85°C and after complete addition the reaction mass was stirred at -78 to -85 0 C for 60 minutes. Reaction completion was checked by TLC/HPLC.
  • the reaction mass was poured into a solution of IN hydrochloric acid (30 ml) and ice cold demineralized water (200 ml). pH was adjusted to 5-6 using IN hydrochloric acid ( ⁇ 20 ml). Methyl tertiarybutyl ether (200 ml) was added and the reaction was stirred at ambient temperature for 15 minutes. Two layers were separated. The aqueous layer was extracted with methyl tertiarybutyl ether (100 ml) and the extraction was added to the main organic layer. The combined organic layer was washed with 0.5 N hydrochloric acid solution (2x100 ml), 1% aqueous sodium hydroxide solution (2x100 ml), 25% brine (2x100 ml) respectively.
  • a freshly prepared Grignard solution (prepared by using 15.76 g of magnesium turnings, 114.9g of l-bromo-4-fluoro benzene, a pinch of iodine and 400 ml of tetrahydrofuran) was added dropwise at -90 to -80 0 C. After complete addition, the reaction mass was stirred at same temperature till reaction completion (monitored by HPLC). The reaction mass was poured into cold demineralized water (750 ml). Methyl tertiary butyl ether (400 ml) was added and the reaction mixture was stirred at ambient temperature for 15 minutes. The product was filtered through hyflo bed.
  • Step-1 Preparation of 4-(4-benzyloxy-phenylVl-(4-fluoro-phenyl)-3-[3[(4-flttoro-phenvI)-3- hydoxy-propyH-azetidin-2-one
  • Step-1 Preparation of l-(4-fluoro-phenyl)-3-f3-(fluoro-phenyl)-3-oxo-propyll-4-(4- hydroxy-phenyl)-azetidin-2-one l-(4-Benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3-(fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one (obtained in Example 7, Method B) was dissolved in ethyl acetate (600 ml). Methanol (600 ml) and palladium-carbon (6.0 g) was added.
  • the eluted chloroform was distilled at 50-55 0 C to obtain l-(4- fluoro-phenyl)-3-[3-(fluoro-phenyl)-3-oxo-propyl]-4-(4-hydroxy-phenyl)-azetidin-2-one.
  • Step-2 Preparation of ezetimibe

Landscapes

  • 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)

Abstract

La présente invention concerne un procédé de préparation, avantageux d'un point de vue industriel, de l'ézétimibe de formule (I) à hauts rendements au moyen de nouveaux intermédiaires d'ester benzylique. Cette invention concerne également un procédé de purification de l'ézétimibe de formule (I).
PCT/IN2008/000072 2007-02-06 2008-02-06 Procédé de préparation de l'ézétimibe extrêmement pur au moyen de nouveaux intermédiaires Ceased WO2008096372A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN234DE2007 2007-02-06
IN234/DEL/2007 2007-02-06
IN216DE2008 2008-01-25
IN216/DEL/2008 2008-01-25

Publications (2)

Publication Number Publication Date
WO2008096372A2 true WO2008096372A2 (fr) 2008-08-14
WO2008096372A3 WO2008096372A3 (fr) 2010-06-24

Family

ID=39682193

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000072 Ceased WO2008096372A2 (fr) 2007-02-06 2008-02-06 Procédé de préparation de l'ézétimibe extrêmement pur au moyen de nouveaux intermédiaires

Country Status (1)

Country Link
WO (1) WO2008096372A2 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009157019A3 (fr) * 2008-06-23 2010-09-30 Ind-Swift Laboratories Limited Préparation d'ezetimdie au moyen de nouveaux intermédiaires allyle
US20110130378A1 (en) * 2008-05-26 2011-06-02 Lek Pharmaceuticals D.D. Ezetimibe process and composition
US8013150B2 (en) * 2005-06-22 2011-09-06 Msn Laboratories Ltd. Process for the preparation of ezetimibe
CN102531985A (zh) * 2011-04-25 2012-07-04 开原亨泰制药股份有限公司 一种制备依泽替米贝关键中间体的新方法
WO2012155932A1 (fr) * 2011-05-17 2012-11-22 Pharmathen S.A. Procédé amélioré pour la préparation d'ézétimibe
CN102854274A (zh) * 2012-09-13 2013-01-02 北京万全德众医药生物技术有限公司 一种用液相色谱法分离测定依折麦布原料及其制剂的方法
CN103373970A (zh) * 2012-04-16 2013-10-30 重庆圣华曦药业股份有限公司 一种依折麦布中间体的合成方法
CN104356041A (zh) * 2014-11-06 2015-02-18 成都森科制药有限公司 依折麦布的制备方法
CN104447473A (zh) * 2014-11-06 2015-03-25 成都森科制药有限公司 依折麦布中间体的制备方法
CN105541690A (zh) * 2015-12-16 2016-05-04 江苏恒盛药业有限公司 一种氮杂环丁酮衍生物的制备方法
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
CN106706818A (zh) * 2015-11-13 2017-05-24 谭惠娟 一种依折麦布中间体光学纯度测定方法
CN107176920A (zh) * 2017-04-19 2017-09-19 上海恒晟药业有限公司 一种依泽麦布的合成新工艺
CN110845384A (zh) * 2019-12-04 2020-02-28 广东省生物医药技术研究所 一种钛络合药物的解离方法及其应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5631365A (en) * 1993-09-21 1997-05-20 Schering Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
CA2613239A1 (fr) * 2005-06-22 2006-12-28 Manne Satyanarayana Reddy Procede ameliore pour la preparation d'ezetimibe
US20070049748A1 (en) * 2005-08-26 2007-03-01 Uppala Venkata Bhaskara R Preparation of ezetimibe

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8013150B2 (en) * 2005-06-22 2011-09-06 Msn Laboratories Ltd. Process for the preparation of ezetimibe
US20110130378A1 (en) * 2008-05-26 2011-06-02 Lek Pharmaceuticals D.D. Ezetimibe process and composition
WO2009157019A3 (fr) * 2008-06-23 2010-09-30 Ind-Swift Laboratories Limited Préparation d'ezetimdie au moyen de nouveaux intermédiaires allyle
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
CN102531985A (zh) * 2011-04-25 2012-07-04 开原亨泰制药股份有限公司 一种制备依泽替米贝关键中间体的新方法
WO2012155932A1 (fr) * 2011-05-17 2012-11-22 Pharmathen S.A. Procédé amélioré pour la préparation d'ézétimibe
CN103373970A (zh) * 2012-04-16 2013-10-30 重庆圣华曦药业股份有限公司 一种依折麦布中间体的合成方法
CN102854274A (zh) * 2012-09-13 2013-01-02 北京万全德众医药生物技术有限公司 一种用液相色谱法分离测定依折麦布原料及其制剂的方法
CN104447473A (zh) * 2014-11-06 2015-03-25 成都森科制药有限公司 依折麦布中间体的制备方法
CN104356041A (zh) * 2014-11-06 2015-02-18 成都森科制药有限公司 依折麦布的制备方法
CN106706818A (zh) * 2015-11-13 2017-05-24 谭惠娟 一种依折麦布中间体光学纯度测定方法
CN106706818B (zh) * 2015-11-13 2018-08-03 广州骏思知识产权管理咨询有限公司韶关分公司 一种依折麦布中间体光学纯度测定方法
CN105541690A (zh) * 2015-12-16 2016-05-04 江苏恒盛药业有限公司 一种氮杂环丁酮衍生物的制备方法
CN105541690B (zh) * 2015-12-16 2018-08-21 江苏恒盛药业有限公司 一种氮杂环丁酮衍生物的制备方法
CN107176920A (zh) * 2017-04-19 2017-09-19 上海恒晟药业有限公司 一种依泽麦布的合成新工艺
CN107176920B (zh) * 2017-04-19 2019-09-20 江苏恒盛药业有限公司 一种依泽麦布的合成新工艺
CN110845384A (zh) * 2019-12-04 2020-02-28 广东省生物医药技术研究所 一种钛络合药物的解离方法及其应用

Also Published As

Publication number Publication date
WO2008096372A3 (fr) 2010-06-24

Similar Documents

Publication Publication Date Title
EP1971573B1 (fr) Procédés de préparation d'intermédiaires utiles pour la préparation de l'ézétimibe
Hiroya et al. Cyclization reactions of 2-alkynylbenzyl alcohol and 2-alkynylbenzylamine derivatives promoted by tetrabutylammonium fluoride
TWI465458B (zh) 製備經葡萄哌喃糖基取代之苯甲基苯衍生物之方法
Burgess et al. Manipulation of substrate-controlled diastereoselectivities in hydroborations of acyclic allylamine derivatives
US20070049748A1 (en) Preparation of ezetimibe
KR20030080620A (ko) 키랄 중간체, 그의 제조방법 및 그를 이용한 HMG-CoA환원저해제의 제조방법
WO2009157019A2 (fr) Préparation d'ezetimdie au moyen de nouveaux intermédiaires allyle
WO2017203474A1 (fr) Procédé de préparation d'intermédiaire de sacubutril
EP3483161A1 (fr) Intermédiaires pour la synthèse de l'entecavir
JP2005520814A (ja) ＨＭＧ−ＣｏＡ還元酵素阻害剤の製造法
WO2009140932A2 (fr) Procédé de production de (3r,4s)-l-(4-fluorophényl)-3-[(3s)-3-(4-fluorophényl)- hydroxypropyl)] -4-(4-hydroxyphényl) -2-azétidinone
WO2003042180A9 (fr) Production d'ester d'acide oxoheptonoique optiquement actif
EP2414326B1 (fr) Intermediaires utilises dans la preparation de 1,4-diphenylazetidinone
NL8500986A (nl) Stereo-geregeld acetoxyazetidinonprocede.
JP4742868B2 (ja) （２ｒ）−２−プロピルオクタン酸の製造方法、その中間体
JP5587350B2 (ja) ラメルテオンの調製方法
US20060063929A1 (en) Process for preparing for imidazopyran derivatives
AU772225B2 (en) Production method of optically active transvinylsulfide alcohol
WO2017168438A1 (fr) Procédé de préparation d'un dérivé cétonique protégé par un allyle pur
JP3803126B2 (ja) 光学活性なトランス体ビニルスルフィドアルコールの製造方法
US6291696B2 (en) Preparation of tris (trimethylsilyl) silylethyl esters
JP2620533B2 (ja) 新規なアミノ酸誘導体
JP4747748B2 (ja) イミダゾピラン誘導体の製法
Coti Investigation on the mechanism of action of pseudoephedrine as a chiral auxiliary: synthesis and use of a novel pseudoephedrine based chiral auxiliary
JPH03236371A (ja) （３ｓ）―２―アゼチジノン誘導体およびその製造方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08710275

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08710275

Country of ref document: EP

Kind code of ref document: A2