WO2007108007A1 - Procede de preparation de l'ezetimibe via un nouvel intermediaire - Google Patents

Procede de preparation de l'ezetimibe via un nouvel intermediaire Download PDF

Info

Publication number
WO2007108007A1
WO2007108007A1 PCT/IN2006/000364 IN2006000364W WO2007108007A1 WO 2007108007 A1 WO2007108007 A1 WO 2007108007A1 IN 2006000364 W IN2006000364 W IN 2006000364W WO 2007108007 A1 WO2007108007 A1 WO 2007108007A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
moles
process according
fluorophenyl
Prior art date
Application number
PCT/IN2006/000364
Other languages
English (en)
Inventor
Arul Ramakrishnan
Nilesh Balkrishna Shrigadi
Tirtha Suresh Prabhavalkar
Amol Narayan Thorat
Original Assignee
Unichem Laboratories Limited
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 Unichem Laboratories Limited filed Critical Unichem Laboratories Limited
Publication of WO2007108007A1 publication Critical patent/WO2007108007A1/fr

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 is related to a process for the preparation of Ezetimibe through a novel intermediate.
  • US 5767115 disclose the hypocholesterolemic activity of hydroxy-substituted azetidinones ⁇ [(3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxy propyl] i 4-(4-hydroxyphenyl)-2-azetidinone] compound of formula (I) and processes for its preparation.
  • WO 97/16424 discloses the process for the preparation of Ezetimibe [formula (I)] by 1 ° alkylating a chiral 3-unsubstitute azetidone with 4-fluorocinnamyl bromide, oxidizing the intermediate s ⁇ formed, followed by chiral reduction and debenzylation.
  • WO 2000/34240 discloses the process which comprises: (a) reacting p- fluorobenzoylbutyric acid with pivaloyl chloride and acylating the product with a chiral auxiliary to obtain a ketone; (b) reducing the ketone in the presence of a chiral 7.0 catalyst to obtain ⁇ a chiral alcohol; (c) reacting the chiral alcohol with an imine in presence of silyl protecting agent, then condensing the protected compound to form a ⁇ -(substituted-amino)amide; (d) cyclisation of the ⁇ -(substituted-atnino)amide with silylating agent and fluoride ion to give protected lactam followed by deprotection.
  • WO2005/066120 and WO2005/049592 disclose the stereoselective reduction of ketone using (-)-B-chlorod ⁇ sopinocampheylborane.
  • R is alkyl or alkylaryl group from C 1 to C 4 .
  • the present invention involves use of less expensive reagent for converting acid of S formula (H) to a novel intermediate, trans-N-methoxy-N-methyl-3(R)-3-[2-oxo-4(S)-
  • the objective is achieved by a process for preparing the Ezetimibe of formula (I), which comprises; s a) reacting a compound of formula (II) with an acid activator in a suitable inert solvent and subsequent reaction with N,O-dimethylhydroxylamine salt, optionally in presence of a suitable base to give compound of formula (V)
  • the compound of formula (II) was prepared according to the process described in i n Bioorganic and Medicinal Chemistry, 1998, 6, 1429-1437 and converted to a novel intermediate of formula (V), which is a useful intermediate for the preparation of Ezetimibe.
  • Step (a) is carried out in a suitable inert solvent such as tetrahydrofuran, diglyme, acetonitrile, dioxane, N,N-dmethylformamide, dimethylsulfoxide, dichloromethane, chloroform, tert-butyl methyl ether, d ⁇ sopropyl ether, however more preferably in dichloromethane and tetrahydrofuran and most preferably in tetrahydrofuran.
  • a suitable inert solvent such as tetrahydrofuran, diglyme, acetonitrile, dioxane, N,N-dmethylformamide, dimethylsulfoxide, dichloromethane, chloroform, tert-butyl methyl ether, d ⁇ sopropyl ether, however more preferably in dichloromethane and tetrahydrofuran and most preferably in tetrahydrofuran.
  • the preferred reaction temperature to activate the acid of formula (II) is below the ⁇ boiling temperature of the solvent used, more preferably between -2O 0 C to boiling temperature of the solvent, still more preferably between about -1O 0 C to 35 0 C and most preferably between 25 0 C to 3O 0 C.
  • the activators for acid of formula (II) are oxalyl chloride, ethyl cbloroformate, methyl chloroformate, pivaloyl chloride, N,N-carbonyldiimidazole (CDI), more preferably 5 ethyl chloroformate, pivaloyl chloride and N,N-carbonyld ⁇ midazole, most preferably
  • N,N-carbonyldiimidazole These acid activators are usually used in excess of 1 to 1.5 moles, more preferably 1.1 to 1.3 moles per mole of the compound of formula (II).
  • Bases used for the reaction are tertiary amines e.g. triethylamine, diethylpropylamine, diisopropylethylamine, N-methylpyrrolidine and N-methylmorpholine, more 0 preferably N-methylmorpholine, N-methylpiperidine, most preferably N- methylmorpholine. It has particularly been proven to use these bases in about 3 to 5 moles excess; mofe preferably in 2.2 to 2.5 moles excess. If N,N-carbonyldiimidazole is used as an acid activator, then no external base is required for the reaction. N,O-dimethylhydroxylamine salt is used in excess of 1 to 2 moles, more preferably 1 to 1.5 moles, most preferably 1,1 to 1.3 moles per mole of compound of formula (II).
  • tertiary amines e.g. triethylamine, diethylpropylamine, diisopropylethylamine, N-methylpyrrol
  • the reaction between N,O-dimethylhydroxylamine salt and the resultant compound after the activation of acid of formula (II) is carried out at O 0 C to 35 0 C.
  • the addition of N,0-dimethylhydroxylamine salt is done at O 0 C.
  • the reaction mixture temperature is maintained at 2O 0 C to 35 0 C, most preferably 25° to 3O 0 C, for about 1 to 4 hours, preferably 2 hours.
  • Step (b) is carried out in a suitable inert solvent like tetrahydrofuran, diglyme, dioxane, diethyl ether, diisopropyl ether and tert-butyl methyl ether, more preferably tetrahydrofuran and diethyl ether, most preferably tetrahydrofuran.
  • a suitable inert solvent like tetrahydrofuran, diglyme, dioxane, diethyl ether, diisopropyl ether and tert-butyl methyl ether, more preferably tetrahydrofuran and diethyl ether, most preferably tetrahydrofuran.
  • Grignard reagent of formula (III) is used in excess of 1 to 5 moles, more preferably 2 to 4 moles, most preferably 2.5 to 3 moles per mole of compound of formula (V).
  • the preferred reaction temperature is below the boiling temperature of the solvent used, more preferably between -2O 0 C to boiling temperature of the solvent, still more preferably betweejn -1O 0 C to 35 0 C and most preferably between -5 0 C to 5 0 C, for about 0.5 to 2 hours, preferably 1 hour.
  • the reaction mixture is acidified and extracted with suitable solvent.
  • Step (c) is carried out in a suitable inert solvents like tetrahydrofuran, dichloromethane, 1,2-dichloro ethane, dioxane, diethyl ether, diisopropyl ether, tert- butyl methyl ether and toluene, more preferably tetrahydrofuran and dichloromethane, most preferably tetrahydrofuran.
  • a suitable inert solvents like tetrahydrofuran, dichloromethane, 1,2-dichloro ethane, dioxane, diethyl ether, diisopropyl ether, tert- butyl methyl ether and toluene, more preferably tetrahydrofuran and dichloromethane, most preferably tetrahydrofuran.
  • the preferred reducing reagent is borane dimethyl sulfide complex with (R)- tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrolo(l,2-c)(l,2,3)-oxazoborolidine (R- MeCBS) or R-diphenylprolinol as a catalyst.
  • the preferable reaction temperature is below the boiling temperature of the solvent used, more preferable between -3O 0 C to boiling temperature of the solvent, still more preferably between -1O 0 C to 35 0 C and most preferably -5 0 C to O 0 C for about 0.5 to 2 hours, preferably 1 hour.
  • Step (d) is carried out in suitable inert solvents like ethanol, methanol, propanol, isopropanol and ethyl acetate more preferably ethanol and methanol, most preferably ethanol.
  • suitable inert solvents like ethanol, methanol, propanol, isopropanol and ethyl acetate more preferably ethanol and methanol, most preferably ethanol.
  • the preferred reaction temperature is below the boiling temperature of the solvent used, more preferably between 1O 0 C to boiling temperature of the solvent, more preferably 2O 0 C to 35 0 C and most preferably 28°C to 3O 0 C, for about 0.5 to 8 hours, preferably 3 hours,
  • reaction mass thus formed was added to a solution of trans-N-methoxy-N-methyl-3(R)-(3- [2-oxo-4(S)-(4-benzyloxyphenyl)-l-(4-fluorophenyl)-azetidinyl]propanamide (11.5g, 0.0249mol) in THF (60ml) over a period of 15-20 minutes under nitrogen atmosphere
  • reaction mixture was cooled to 1O 0 C and 0.5N aqueous HCl (10ml) was added at 1O 0 C to 15 0 C. Reaction mixture was concentrated under vacuum at 4O 0 C. Dichloro methane (100ml) was added to the concentrated solution and washed with 5% aqueous sodium bicarbonate (2x3 OmI)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de l'ézétimibe via un nouvel intermédiaire. L'acide trans-3(R)-(3-[2-oxo-4(S)-(4-benzyloxyphényl)-1-(4-fluorophényl)-azétidinyl]propanoïque est converti en trans-N-méthoxy-N-méthyl-3(R)-3-[2-oxo-4(S)-(4-benzyloxyphényl)-1-(4-fluorophényl)-azétidinyl]propanamide et l'intermédiaire résultant est soumis à une réaction de Grignard de façon à obtenir la trans-1-(4-fluorophényl)-3(R)-[3-oxo-3-(4-fluorophényl)propyl]-4(S)-(4-benzyloxyphényl)-2-azétidinone. La réduction de la trans-1-(4-fluorophényl)-3(R)-[3-oxo-3-(4-fluorophényl)propyl]-4(S)-(4-benzyloxyphényl)-2-azétidinone, suivie de la débenzylation donne l'ézétimibe. L'invention concerne également la préparation de l'intermédiaire rencontré dans le procédé susmentionné.
PCT/IN2006/000364 2006-03-23 2006-09-12 Procede de preparation de l'ezetimibe via un nouvel intermediaire WO2007108007A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN412/MUM/2006 2006-03-23
IN412MU2006 2006-03-23

Publications (1)

Publication Number Publication Date
WO2007108007A1 true WO2007108007A1 (fr) 2007-09-27

Family

ID=38522080

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000364 WO2007108007A1 (fr) 2006-03-23 2006-09-12 Procede de preparation de l'ezetimibe via un nouvel intermediaire

Country Status (1)

Country Link
WO (1) WO2007108007A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008089984A3 (fr) * 2007-01-24 2008-09-18 Krka Procédé de fabrication de l'ézétimibe et de ses dérivés
US20100010212A1 (en) * 2005-09-08 2010-01-14 Vinod Kumar Kansal Processes for the preparation of (3R,4S)-4-((4-benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-2-azetidinone, an intermediate for the synthesis 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
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
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
WO2017168438A1 (fr) * 2016-03-31 2017-10-05 Ind-Swift Laboratories Limited Procédé de préparation d'un dérivé cétonique protégé par un allyle pur

Citations (3)

* 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
US6207822B1 (en) * 1998-12-07 2001-03-27 Schering Corporation Process for the synthesis of azetidinones
WO2004005247A1 (fr) * 2002-07-05 2004-01-15 Astrazeneca Ab Derives de diphenylazetidinone pour le traitement de troubles de metabolisme lipidique

Patent Citations (3)

* 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
US6207822B1 (en) * 1998-12-07 2001-03-27 Schering Corporation Process for the synthesis of azetidinones
WO2004005247A1 (fr) * 2002-07-05 2004-01-15 Astrazeneca Ab Derives de diphenylazetidinone pour le traitement de troubles de metabolisme lipidique

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100010212A1 (en) * 2005-09-08 2010-01-14 Vinod Kumar Kansal Processes for the preparation of (3R,4S)-4-((4-benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-2-azetidinone, an intermediate for the synthesis of ezetimibe
WO2008089984A3 (fr) * 2007-01-24 2008-09-18 Krka Procédé de fabrication de l'ézétimibe et de ses dérivés
CN102285906A (zh) * 2007-01-24 2011-12-21 克尔克公司 依泽替米贝的制备方法和其的衍生物
EA017349B1 (ru) * 2007-01-24 2012-11-30 Крка Способ получения эзетимиба и его производных
CN102285906B (zh) * 2007-01-24 2014-11-19 克尔克公司 依泽替米贝的制备方法和其的衍生物
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
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
WO2017168438A1 (fr) * 2016-03-31 2017-10-05 Ind-Swift Laboratories Limited Procédé de préparation d'un dérivé cétonique protégé par un allyle pur

Similar Documents

Publication Publication Date Title
US8178665B2 (en) Process for the production of ezetimibe and intermediates used in this process
WO2007108007A1 (fr) Procede de preparation de l'ezetimibe via un nouvel intermediaire
US6207822B1 (en) Process for the synthesis of azetidinones
EP1971573B1 (fr) Procédés de préparation d'intermédiaires utiles pour la préparation de l'ézétimibe
KR101156588B1 (ko) 에제티밉의 제조방법 및 이에 사용되는 중간체
CZ227592A3 (en) Method of taxol side chain asymmetric synthesis
US20110046389A1 (en) Intermediates for the preparation of (3r, 4s)-1-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3-hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone
WO2009157019A2 (fr) Préparation d'ezetimdie au moyen de nouveaux intermédiaires allyle
WO2009140932A2 (fr) Procédé de production de (3r,4s)-l-(4-fluorophényl)-3-[(3s)-3-(4-fluorophényl)- hydroxypropyl)] -4-(4-hydroxyphényl) -2-azétidinone
CZ302395B6 (cs) Zpusob výroby (3R,4S)-1-(4-fluorfenyl)-3-[(3S)-3-(4-fluorfenyl)-3-hydroxypropyl)]-4-(4-hydroxyfenyl)-2-azetidinonu
EP2414326B1 (fr) Intermediaires utilises dans la preparation de 1,4-diphenylazetidinone
US6833458B2 (en) Practical syntheses of chiral trans-3, 4-disubstituted piperidines and the intermediates
US20080200699A1 (en) Method for Preparing Docetaxel
JP5587350B2 (ja) ラメルテオンの調製方法
JPS6328423B2 (fr)
CN107118144B (zh) 依替米贝及其中间体的还原制备工艺
WO2004043961A1 (fr) Procede de production d'un compose de carbapenem pour l'administration par voie orale
JPH09507844A (ja) キラル補助物質におけるまたはこれに関する改良
WO2012114926A1 (fr) Composé de thioamide, procédé de production d'un composé de thioamide, procédé de production d'un dérivé d'acétate de [(4r,6r)-6-aminoéthyl- 1,3-dioxane-4-yle], et procédé de production d'atorvastatine
JP3503451B2 (ja) オキサゾリジン−２−オン誘導体の製造方法
Arai et al. Diastereoselective Imino–Aldol Condensation of Chiral 3-(p-Tolylsulfinyl)-2-furaldimine and Ester Enolates
JP3748933B2 (ja) １−置換アゼチジノン誘導体の製造法
HU216634B (hu) N-szubsztituált 2-azetidinonok mint intermedierek az N-szubsztituálatlan 2-azetidinonok új előállítási eljárásában
JP5059355B2 (ja) オキサゾリジン誘導体の製造方法
JP4066100B2 (ja) Ｎ−アシル含窒素環状ケトン類の製造方法

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: 06842753

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06842753

Country of ref document: EP

Kind code of ref document: A1