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WO2012076030A1 - Procédé de préparation de composés intermédiaires utiles dans la préparation de l'ézétimibe - Google Patents

Procédé de préparation de composés intermédiaires utiles dans la préparation de l'ézétimibe Download PDF

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Publication number
WO2012076030A1
WO2012076030A1 PCT/EP2010/007529 EP2010007529W WO2012076030A1 WO 2012076030 A1 WO2012076030 A1 WO 2012076030A1 EP 2010007529 W EP2010007529 W EP 2010007529W WO 2012076030 A1 WO2012076030 A1 WO 2012076030A1
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Prior art keywords
formula
compound
fluorophenyl
process according
hydroxylamine
Prior art date
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Ceased
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PCT/EP2010/007529
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English (en)
Inventor
Theocharis V. Koftis
Thanos Andreou
Asteria Zitrou
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Pharmathen SA
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Pharmathen SA
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Priority to PCT/EP2010/007529 priority Critical patent/WO2012076030A1/fr
Publication of WO2012076030A1 publication Critical patent/WO2012076030A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms

Definitions

  • the present invention relates to a novel process for the preparation of (3R, 45)-4-(4- (benzyloxy)phenyl)-l-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)azetidin-2-one, which is an intermediate compound useful in the process for the preparation of Ezetimibe, and novel intermediates obtained thereof.
  • Ezetimibe is an agent used for reducing plasma cholesterol level. Ezetimibe is also used in combination with Simvastatin, when statins alone do not control cholesterol levels.
  • Ezetimibe is chemically designated as (3R, 4S)-l-(4-fluorophenyl)-3-((5)-3-(4-fluorophenyl)-3- hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one and is presented by the chemical structure of Formula I.
  • Ezetimibe can be further obtained by reducing the ketone functional group and removing the hydroxy-protecting group.
  • Ezetimibe was first disclosed in EP-B-0720599, wherein a laborious process involving several steps and providing unsatisfactorily low yield of Ezetimibe is described. First an azetidinone ring is formed by cyclizing the coupling product of methyl 5-oxo-5[(5)-2-oxo-4-phenyl-oxazolidine- 3-yl]pentanoate and [4-(benzyloxy)benzylidene]-(4-fluorophenyl)amine.
  • WO-A-2007/072088 discloses a process for the preparation of Ezetimibe, wherein no carbonyl chloride intermediate is used.
  • the starting material 5-(4-fluorophenyl)- 5-oxopentanoic acid is first converted into a ketal protecting form, which is then first reacted with a chiral oxazolidinone.
  • the titanium enolate of said oxazolidinone is subsequently reacted with [4-(benzyloxy)benzylidene]-(4-fluorophenyl)amine, followed by transamidation to form the azetidinone ring.
  • the ketal functional group is hydrolyzed to obtain intermediate compound of Formula VII.
  • acid chloride intermediate is not used in this process, still the yields of the key coupling reaction are moderate, due to ketal protecting group employed, which is labile when subjected to the described enolization conditions.
  • WO-A-2010/071358 discloses a process for the preparation of Ezetimibe, wherein (5)-l-(4- fluorophenyl)-5-(2-oxo-4-phenyloxazolidin-3-yl)pentane-l,5-dione is reacted with O- trimethylsilyl cyanohydrine to obtain a novel ketone-protected intermediate. Said intermediate is subsequently subjected to enolization followed by condensation with a trimethylacetyl protected imine and cyclization to obtain intermediate compound of Formula VII.
  • an object of the present invention to provide an improved process for the preparation of (3R, 45)-4-(4-(benzyloxy)phenyl)-l-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3- oxopropyl)azetidin-2-one (compound of Formula VII) as a key intermediate for the synthesis of Ezetimibe, which overcomes the deficiencies of the prior art processes and results to a cost effective industrial production without sacrificing the yield and quality of the product.
  • Another object of the present invention is to provide novel intermediate compounds which are stable under standard enolization conditions, yet sufficiently reactive to provide the key products in high yield and purity, therefore efficient when used in the process for the preparation of Ezetimibe.
  • Another object of the present invention is to provide compounds of Formula III, V, VI, and VII as defined in claims 13, 16, 19 and 22.
  • Another object of the present invention is to provide novel intermediate compounds of Formula Ilia, chemically designated as (5)-3-(5-(4-fluorophenyl)-5-(hydroxyimino)pentanoyl)-4- phenyloxazolidin-2-one and Formula Illb, chemically designated as (S)-3-(5-(tert- butyldimethylsilyloxyimino)-5-(4-fluorophenyl)pentanoyl)-4-phenyloxazolidin-2-one.
  • a further object of the present invention is to provide novel intermediate compounds of Formula Va, chemically designated as (5)-3-((S)-2-((S)-(4-(benzyloxy)phenyl)(4- fluorophenylamino)methyl)-5-(4-fluorophenyl)-5-(hydroxyimino)pentanoyl)-4- phenyloxazolidin-2-one, and compound of Formula Vb, chemically designated as (S)-3-((5)-2- ((5)-(4-(benzyloxy)phenyl)(4-fluorophenylamino)methyl)-5-(tert-butyldimethylsilyloxyimino)- 5-(4-fluorophenyl)pentanoyl)-4-phenyloxazolidin-2-one.
  • Another object of the present invention is to provide novel intermediate compounds of Formula Via, chemically designated as (3R,45)-4-(4-(benzyloxy)phenyl)-l-(4-fluorophenyl)-3-(3-(4- fluorophenyl)-3-(hydroxyimino)propyl)azetidin-2-one, and compound of Formula VIb, chemically designated as (3R,45 -4-(4-(benzyloxy)phenyl)-3-(3-(tert- butyldimethylsilyloxyimino)-3-(4-fluorophenyl)propyl)-l-(4-fluorophenyl)azetidin-2-one.
  • the present invention relates to a novel process for the preparation of Formula VII, which is an intermediate compound useful for the preparation of Ezetimibe.
  • the process for the preparation of Formula VII comprises the following steps:
  • hydroxylamine compound selected from hydroxylamine, hydroxylamine trimethylsilylether, hydroxylamine tert-butyldimethylsilyl ether, hydroxylamine tert-butyldiphenylsilyl ether, preferably hydroxylamine.
  • a protecting agent can be optionally added to the reaction of (S')-N-acyl-oxazolidide of Formula II with a hydroxylamine compound.
  • Said protecting agent is selected from trialylsilylchloride of formula R'R ⁇ SiCl, in which R 1 , R 2 and R 3 represent independently C 1-6 alkyl groups, preferably R 1 and R 2 represent a methyl group and R 3 represents a tert-butyl group.
  • the solvent used in the reaction of (S)-N-acyl-oxazolidide of Formula ⁇ with a hydroxylamine compound is selected from pyridine, ethanol, methanol or a mixture thereof.
  • the preferred solvent is pyridine.
  • Free oxime of Formula Ilia is isolated as a white crystalline solid after aqueous workup.
  • the preferred solvent for the crystallization is a 1 : 1 v/v mixture of ethyl acetate and cyclohexane.
  • R represents R 1 R 2 R 3 Si-, wherein R 1 , R 2 and R 3 are independently C 1-6 alkyl groups, most preferably R 1 and R 2 represent a methyl group and R 3 represents a tert-butyl group.
  • the conditions employed for this protection may be selected from standard hydroxyl group silylation reagent combinations such as triethylamine/N,N'-dimethylaminopyridine/teri-butyldimethylsilylchloride and imidazole/N,N'-dimethylaminopyridine/tert-butyldimethylsilylchloride.
  • the solvent is selected from methylene chloride or dimethylformamide, preferably methylene chloride.
  • compound of Formula II is consecutively reacted with hydroxylamine and an adequate trialkylsilylchloride in a basic solvent such as pyridine, providing the protected oxime of Formula III, wherein R is a hydroxyl protecting group, after slightly acidic aqueous workup.
  • a basic solvent such as pyridine
  • the preferred trialkylsilylchloride is tert-butyldimethylsilylchloride.
  • TBS-protected oxime of Formula Illb may be isolated in high yields through crystallization from ethanol.
  • the obtained oximes of general formula III are separately reacted with an imine of formula IV, in the presence of a Lewis acid selected from titanium tetrachloride, titanium tetraisopropoxide, or a mixture thereof and an organic base.
  • a Lewis acid selected from titanium tetrachloride, titanium tetraisopropoxide, or a mixture thereof and an organic base.
  • Base for this reaction is selected form substituted amines, such as triethylamine, diethylisopropylamine, sparteine, preferably diethylisopropylamine.
  • reaction is carried out in chlorinated hydrocarbon solvents such as ethylene chloride and methylene chloride, preferably methylene chloride.
  • chlorinated hydrocarbon solvents such as ethylene chloride and methylene chloride, preferably methylene chloride.
  • a mildly acidic aqueous workup is followed by standard extraction procedure and the compounds of general formula V are isolated through precipitation from cold ethanol.
  • a compound of Formula Va is obtained.
  • Purified compound of Formula Va is obtained through column chromatography eluted with 1% MeOH/CH 2 Cl 2 or by crystallization from methanol.
  • step (a) Compound of general formula V as obtained in step (a) is treated with a trimethylsilyl donor and converted to the N-TMS functionalized intermediate.
  • a fluoride anion source triggers the nucleophilic attack on the gamma-positioned carbonyl which results in transamidation and formation of the beta-lactam, with concomitant regeneration of the chiral auxiliary which may be recycled. Further addition of fluoride anion source results in the deprotection of the oxime if needed.
  • the trimethylsilyl donor may be selected from N,0-bis(trimethylsilyl)acetamide (BSA) and N,0-bis(trimethylsilyl)trifluoroacetamide (BSTFA), preferably BSA.
  • the fluoride anion source is selected from tetra-N-butylammonium fluoride (TBAF), CsF, KF, preferably TBAF.
  • the molar ratio of the fluoride anion source with respect to the starting compound of Formula V is between 0.1: 1 and 2.5: 1, preferably between 0.1 : 1 and 1.8: 1.
  • the reaction is carried out in an aprotic solvent selected from toluene and acetonitrile, preferably toluene.
  • the reaction mixture temperature may be between 0 and 100°C, preferably between 10 and 80°C, more preferably between 25 and 60°C.
  • Purified compound of Formula Via is obtained through column chromatography using 40% ethyl acetate:cyclohexane as eluent or by crystallization from methanol.
  • Purified compound of Formula VIb is obtained through column chromatography using 20-30% ethyl acetate: cyclohexane as eluent.
  • the oxime beta-lactam compounds of general Formula VI are converted to the target ketone compound of Formula VII.
  • Various methods for the regeneration of carbonyl compounds from their corresponding oximes may be selected from conventional deoximation conditions in aqueous and non-aqueous solution, heterogenous and solvent-free conditions and ultrasound, ultraviolet and microwave irradiation-assisted transformations.
  • the preferred conditions comprise the use of an inorganic acid in aqueous formaldehyde in the presence of a polar aprotic solvent.
  • the preferred inorganic acid is hydrochloric acid.
  • the preferred solvent is tetrahydrofuran.
  • the parent ketone of Formula VII is obtained as a single compound, regardless of the E/Z isomeric ratio of the starting oximes. This is further confirmed by the examples provided below where the oxime intermediates are used without purification.
  • Compound of Formula VII can be reduced according to methods described in EP-B-0720599.
  • Chiral catalysts used are methyl oxazaborolidine (Me-CBS), phenyl oxazaborolidine (Ph-CBS), etc, and BH 3 complexes are used as hydride donors, such as BH3-DMS, BH3-diethylaniline and BH 3 -THF.
  • the preferred solvent for this reaction is toluene.
  • Deprotection of the obtained reduced compound can also be carried out, if needed, according to methods described in EP-B-0720599, with hydrogen gas and a Pd catalyst such as Pd/C.
  • IR (KBr) cm -1 3473, 3290, 3248, 3065, 2924, 1784, 1708, 1598, 1510, 1458, 1376, 1327, 1208, 1160, 1082, 1068, 926, 912, 835, 772, 764, 727, 708, 589, 527, 511 ;
  • s, d, t and m are referred to singlet, doublet, triplet and multiplet peaks respectively
  • phenyloxazolidin-2-one In a heatgun-dried round bottom flask containing 21mL methylene chloride, 2.3mL TiCl 4 are added at 0°C, followed by 1.9mL Ti(0'Pr) 4 and the resulting creamy suspension is stirred at 0°C for 30 minutes. lO.Og of protected oxime IHb are dissolved in 30mL methylene chloride and added dropwise at 0°C to the above mixture, stirring continues for 10 minutes then 8.0mL diisopropylethylamine are slowly added at 0°C and the resulting red enolate mixture is further stirred for 1 hour at this temperature.
  • the organic layer is washed consecutively with lOmL saturated NHjCl, lOmL saturated NaHC0 3 , lOmL water and lOmL brine, dried over sodium sulfate and evaporated under reduced pressure to afford crude VIb as a mixture of isomers.
  • the residue is purified by silica gel column chromatography using 20-30% ethyl acetate:cyclohexane as eluent, affording 1.5g of the oxime VIb as colorless gum.
  • oxime of formula Via 500mg of oxime of formula Via are dissolved in lOmL THF and 5mL 35% aqueous formaldehyde before the addition of 5mL of HC1 IN.
  • the resulting colorless, biphasic mixture is stirred vigorously at room temperature during 6 hours until the organic layer becomes orange- yellow. It is then diluted with lOmL ethyl acetate and neutralized with saturated aqueous sodium bicarbonate.
  • the aqueous layer is extracted with 2x1 OmL ethyl acetate and the combined organic layers are washed with lOmL water and lOmL brine, dried over sodium sulfate, filtered and evaporated.
  • the residue is purified through silica gel column chromatography to provide 312mg of ketone VII as a yellow oil.
  • aqueous layer is extracted with 2x1 OmL ethyl acetate and the combined organic layers are washed with lOmL water and lOmL brine, dried over sodium sulfate, filtered and evaporated to provide 307mg of pure ketone VII as an oily solid.
  • the solid is then dissolved in 15mL THF and lOmL 35% aqueous formaldehyde before the addition of 0.8mL of concentrated HC1.
  • the resulting colorless, biphasic mixture is stirred vigorously at room temperature during 3 hours until the organic layer becomes orange-yellow. It is then diluted with 30mL ethyl acetate and neutralized with saturated aqueous sodium bicarbonate.
  • the aqueous layer is extracted with 2xl0mL ethyl acetate and the combined organic layers are washed with lOmL water and lOmL brine, dried over sodium sulfate, filtered and evaporated to provide l.lg of ketone VII.
  • the process of the present invention makes use of oximes as a carbonyl protecting group, previously undisclosed with respect to this type of substrates or these reaction conditions.
  • the preparation of the oxime intermediates is quantitative, their isolation is paradigmatic as crystalline solids, their use as enolate precursors is advantageous over other carbonyl-masking moieties in terms of stability and reactivity and their reversion to the parent carbonyl is uneventful under standard conditions.
  • the reaction sequences, the reagents and the isolation procedures of the present process are cost-effective, scalable and of almost no safety concern, therefore suitable for industrial application.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Cette invention concerne un procédé amélioré de préparation de (3R, 4S)-4-(4- (benzyloxy)phényl)-1-(4-fluorophényl)-3-(3-(4-fluorophényl)-3-oxopropyl)azétidin-2-one, qui est un intermédiaire clé pour la préparation de l'ézétimibe, et concerne l'utilisation desdits nouveaux composés intermédiaires.
PCT/EP2010/007529 2010-12-10 2010-12-10 Procédé de préparation de composés intermédiaires utiles dans la préparation de l'ézétimibe Ceased WO2012076030A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107488190A (zh) * 2016-06-10 2017-12-19 山东新时代药业有限公司 一种依折麦布中间体及其制备方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045406A1 (fr) * 1996-05-31 1997-12-04 Schering Corporation Azetidinones synthetisees par synthese enantioselective a base de 3-hydroxy gamma-lactone
EP0720599B1 (fr) 1993-09-21 1999-05-19 Schering Corporation Composes d'azetidinone hydroxy-substitues efficaces en tant qu'agents hypocholesterolemiques
WO2000034240A1 (fr) * 1998-12-07 2000-06-15 Schering Corporation Procede relatif a la synthese d'azetidinones
WO2007072088A1 (fr) 2005-12-20 2007-06-28 Richter Gedeon Nyrt. Procede pour la production d'ezetimibe et intermediaires utilises dans ce procede
WO2007119106A2 (fr) * 2005-12-22 2007-10-25 Medichem, S.A. Procédés de préparation de composés intermédiaires utilisés dans la préparation de l'ézétimibe
WO2008106900A1 (fr) * 2007-03-02 2008-09-12 Zentiva, A.S. Procédé de fabrication de (3r, 4s) -1- (4-fluorophényle) -3- [ (3s) -3- (4 -fluorophényle) -3-hydroxypropyle) ] -4- (4-hydroxyphényle) -2-azétidinone
WO2008151324A1 (fr) * 2007-06-07 2008-12-11 Teva Pharmaceutical Industries Ltd. Procédés de réduction pour la préparation d'ézétimibe
WO2010071358A2 (fr) 2008-12-17 2010-06-24 Hanmi Pharm. Co., Ltd. Procédé de préparation d'ézétimibe et intermédiaires utilisés dans ce dernier
WO2010113182A1 (fr) * 2009-03-31 2010-10-07 Lupin Limited Intermediaires utilises dans la preparation de 1,4-diphenylazetidinone

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0720599B1 (fr) 1993-09-21 1999-05-19 Schering Corporation Composes d'azetidinone hydroxy-substitues efficaces en tant qu'agents hypocholesterolemiques
WO1997045406A1 (fr) * 1996-05-31 1997-12-04 Schering Corporation Azetidinones synthetisees par synthese enantioselective a base de 3-hydroxy gamma-lactone
WO2000034240A1 (fr) * 1998-12-07 2000-06-15 Schering Corporation Procede relatif a la synthese d'azetidinones
WO2007072088A1 (fr) 2005-12-20 2007-06-28 Richter Gedeon Nyrt. Procede pour la production d'ezetimibe et intermediaires utilises dans ce procede
WO2007119106A2 (fr) * 2005-12-22 2007-10-25 Medichem, S.A. Procédés de préparation de composés intermédiaires utilisés dans la préparation de l'ézétimibe
WO2008106900A1 (fr) * 2007-03-02 2008-09-12 Zentiva, A.S. Procédé de fabrication de (3r, 4s) -1- (4-fluorophényle) -3- [ (3s) -3- (4 -fluorophényle) -3-hydroxypropyle) ] -4- (4-hydroxyphényle) -2-azétidinone
WO2008151324A1 (fr) * 2007-06-07 2008-12-11 Teva Pharmaceutical Industries Ltd. Procédés de réduction pour la préparation d'ézétimibe
WO2010071358A2 (fr) 2008-12-17 2010-06-24 Hanmi Pharm. Co., Ltd. Procédé de préparation d'ézétimibe et intermédiaires utilisés dans ce dernier
WO2010113182A1 (fr) * 2009-03-31 2010-10-07 Lupin Limited Intermediaires utilises dans la preparation de 1,4-diphenylazetidinone

Non-Patent Citations (1)

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Title
HESK D ET AL: "Synthesis of 3H, 14C and 13C6 labelled Sch 58235", JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, JOHN WILEY, CHICHESTER, GB, vol. 45, 1 January 2002 (2002-01-01), pages 145 - 155, XP002443239, ISSN: 0362-4803, DOI: DOI:10.1002/JLCR.539 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107488190A (zh) * 2016-06-10 2017-12-19 山东新时代药业有限公司 一种依折麦布中间体及其制备方法

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