WO2015039675A1 - Nouveau procédé de préparation d'intermédiaires d'ézétimibe - Google Patents

Nouveau procédé de préparation d'intermédiaires d'ézétimibe Download PDF

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Publication number
WO2015039675A1
WO2015039675A1 PCT/EP2013/002848 EP2013002848W WO2015039675A1 WO 2015039675 A1 WO2015039675 A1 WO 2015039675A1 EP 2013002848 W EP2013002848 W EP 2013002848W WO 2015039675 A1 WO2015039675 A1 WO 2015039675A1
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WO
WIPO (PCT)
Prior art keywords
process according
formula
diphenylethylenediamine
compound
alkyl
Prior art date
Application number
PCT/EP2013/002848
Other languages
English (en)
Inventor
Theocharis V. KOFTIS
Efstratios Neokosmidis
Efi GIOTI
Elli Alexandraki
Panagiota Mandalou
Aristotelis Menisiou
Thanos Andreou
Original Assignee
Pharmathen S.A.
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 Pharmathen S.A. filed Critical Pharmathen S.A.
Priority to PCT/EP2013/002848 priority Critical patent/WO2015039675A1/fr
Publication of WO2015039675A1 publication Critical patent/WO2015039675A1/fr

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Classifications

    • 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

Definitions

  • the present invention relates to novel process for the preparation of compounds useful as intermediates for the production of ezetimibe.
  • 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
  • Ezetimibe was first disclosed in EP 0720599 and the laborious process for its preparation addresses three focal points of the synthesis using well-established and name-accredited procedures (Scheme 1).
  • the configuration of the feta-lactam ring is ensured by Evans oxazolidinone enolate chemistry (step a), the 4-fluorobenzyl group of the side chain is introduced through Negishi coupling (step d) and the alcohol moiety is stereoselectively constructed under influence of the Corey-Bakshi-Shibata chiral oxazaborolidine complex (step e).
  • the overall process employs expensive reagents but affords low yields, while extensive purification steps are needed in order to remove the process-related impurities.
  • the object of the present invention is to provide an improved process for the preparation of compounds of general Formula III to be used as key intermediates for the synthesis of ezetimibe.
  • X is selected from hydrogen and halogen
  • Y is selected from -OR' , -NR R or a chiral auxiliary group.
  • Chiral auxiliary groups are repre nted by the formula
  • R 1 , R 2 and R 3 may be independently selected from Cj-C alkyl, Q-C6 alkoxy, aryl or benzyl groups or may together form a cyclic group, optionally containing a heteroatom such as O; and each Z is independently selected from O and S.
  • Chiral auxiliary groups include, but are not limited to, the following structures
  • the process according to the present invention comprises a previously undisclosed asymmetric transfer hydrogenation (ATH) protocol for the stereoselective reduction of a ketone of Formula II to form an alcohol of Formula III.
  • ATH asymmetric transfer hydrogenation
  • a further object of the present invention is to provide an improved process for the preparation of compounds of Formula III, wherein a ketone of Formula II is converted to the alcohol of Formula III by an improved asymmetric transfer hydrogenation protocol which comprises the use of aqueous media and an organic ion pair additive.
  • Yet another object of the present invention is to provide the intermediate compounds of Formula III adequately functionalized, in high yield and purity, therefore efficient when used in the process for the preparation of ezetimibe.
  • a preferred object of the present invention is to provide an improved asymmetric transfer hydrogenation (ATH) protocol for the stereoselective reduction of a ketone of Formula Ila to form an alcohol of Formula Ilia.
  • ATH asymmetric transfer hydrogenation
  • the present invention relates to a novel process for the preparation of compounds of Formula III, which are intermediate compounds useful for the preparation of ezetimibe.
  • the process for the preparation of compounds of Formula III comprises the Asymmetric Transfer Hydrogenation of a compound of Formula II to provide a compound of Formula III,
  • X is selected from hydrogen and halogen
  • Y is selected from -OR 1 , -NR 1 R 2 or a chiral auxiliary group.
  • Chiral auxiliary groups are represented b the formula R , R and R J may be independently selected from Q-C 6 alkyl, C ! -C 6 alkoxy, aryl or benzyl groups or may together form a cyclic group, optionally containing a heteroatom such as O; and each Z is independently selected from O and S.
  • compounds of Formula II include, but are not limited to
  • the Asymmetric Transfer Hydrogenation (ATH) of aryl-ketones has been extensively studied in the literature.
  • the key reaction features of the ATH are the catalyst, characterized by a chiral ligand and a metal center, the hydrogen donor and the reaction medium.
  • the current paradigm for the ATH of such substrates endorses the catalysts that incorporate Ru, Rh or Ir as a metal center and a member of the 1 ,2-diphenylethylenediamine (DPEN) family as a chiral ligand.
  • Catalyst loadings of 50:1 to 1000:1 (substrate: catalyst molar ratio) are usually required.
  • the triethylamine:formic acid mixture commonly in a 5:2 ratio, is being preferred over alternative hydrogen donors and is frequently used as the only reaction medium.
  • a compound of Formula II and an Asymmetric Transfer Hydrogenation catalyst are treated with a hydrogen donor in the presence of an amine base in an organic solvent.
  • the catalyst used in the process according to the present invention may be selected from suitable ATH catalysts employed in the prior art, usually represented by the formula MX(L1)(L2) in the relevant literature, wherein M is a metal center, X is a halogen atom, LI is a rj 5 - or ⁇ 6 - arene ligand and L2 is a chiral ligand.
  • M may be selected from Ru, Rh or Ir, and the preferred metal center is X may be selected from CI, Br and I, and the preferred halogen is CI.
  • LI may be selected from arene ligands such as benzene, p-cymene, mesitylene, 1,3,5- triethylbenzene, hexamethylbenzene, cyclopentadienyl and 1,2,3,4,5- pentamethylcyclopentadienyl, and the preferred arenes are p-cymene and mesitylene.
  • L2 may be selected from chiral diamine ligands of the structure shown below:
  • R 4 is selected from C6 to C14 aryl or C5 to C12 heteroaryl rings or CI to C12 alkyl groups, optionally substituted with one or more CI to C12 alkyl, halogen or CI to C 12 alkoxy groups, where the two R 4 groups may optionally together form a ring; and
  • A is selected from C6 to C14 aryl rings, C5 to C12 heteroaryl rings, CI to C12 linear, monocyclic or polycyclic alkyl groups, optionally substituted with one or more CI to C12 alkyl, halogen or CI to C 12 alkoxy groups, and secondary amines, such as pyrrolidine, piperidine and morpholine.
  • the R 4 group of ligand L2 is a phenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl or 4-methoxyphenyl group.
  • the -S0 2 -A group of ligand L2 is a p-toluenesulfonyl, methanesulfonyl, benzenesulfonyl, pentafluorophenylsulfonyl, (-)-camphorsulfonyl, (+)-camphorsulfonyl, piperidyl-N-sulfonyl, pyrrolidyl-N-sulfonyl or morpholyl-N-sulfonyl group.
  • n is an integer selected from 0, 1, 2 or 3;
  • Y is selected from CH 2 or O
  • R is selected from H or a CI to C3 alkyl group
  • Suitable catalysts may be prepared using published methods or are available commercially.
  • the catalyst complex may be prepared previously and optionally isolated, or may be generated as a part of the Asymmetric Transfer Hydrogenation reaction, optionally in the same container ⁇ one-pot reactions).
  • the catalyst loading is usually expressed by the substrate-to-catalyst molar ratio (S:C or S/C), which is calculated as the ratio of the molar quantities of the substrate and the catalyst employed during the attempted Asymmetric Transfer Hydrogenation reaction.
  • the main components of the chiral catalyst, the metal center and the chiral ligand, are significantly more expensive than the rest of the raw materials used in the Asymmetric Transfer Hydrogenation transformation.
  • the catalyst loading is unequivocally the major cost- driving factor of this kind of reactions.
  • lower catalyst loadings reduce the potential for carry-over of residual heavy metals to the next steps of the synthesis, thereby contributing to the quality of the final product and to the overall efficiency of the process by suppressing avoidable analytical strain.
  • the hydrogen donor of the Asymmetric Transfer Hydrogenation may be selected from hydrogen donors known in the literature as suitable for transfer hydrogenations, such as formic acid or a salt or derivative of formic acid, cyclohexene or I-methylcyclohexane.
  • the preferred hydrogen donor is formic acid or a salt thereof.
  • the amine base used in the reaction is a tertiary amine and the preferred amine base is triethylamine.
  • the organic solvent used in the reaction is selected from ethers, such as diethylether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, t-butylmethylether (TBME), diisopropylether, cyclopentylmethylether, glymes, such as monoglyme and diglyme, dioxane, saturated or unsaturated hydrocarbons, such as hexanes, heptanes, benzene, toluene, chlorinated hydrocarbons, such as dichloromethane, dichloroethanes and chloroform, acetate esters such as ethylacetate, propylacetates, polar aprotic solvents, such as DMSO, DMF, DMAC.
  • ethers such as diethylether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, t-butylmethylether (TBME), diisopropylether, cycl
  • the preferred solvents are ethers and glymes, and even more preferred are THF and TBME.
  • the reaction temperature may range between 0 °C and the boiling point of the solvent or solvent mixture, preferably between about 30°C and the boiling point of the solvent or solvent mixture.
  • a compound of Formula II and an Asymmetric Transfer Hydrogenation catalyst are treated with a hydrogen donor in the presence of an organic ion pair additive in an aqueous reaction medium containing an organic solvent.
  • Adequate additives may be selected from tetra-N-substituted ammonium salts and hydroxides, -, according to the formula R 4 NX, wherein each R may be independently selected from CI to CI 6 alkyl groups or benzyl groups, and X may be a halogen or a hydroxyl group.
  • organic ion pair additives may be used in their pure or hydrate forms, in an aqueous or non-aqueous solution, grafted or attached to a polymeric structure, as in the case of basic ion-exchange polymers.
  • Suitable organic ion pair additives are tetramethylammonium hydroxide, tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium hydroxide, tetraethylammonium chloride, tetraethylammonium bromide, tetrabutylammonium hydroxide, tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium hydroxide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium hydroxide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, hexadecyltrimethylammonium hydroxide, hexadecyltrimethylammonium chloride, hexadec
  • the preferred organic ion pair additives are tetra-alkylammonium hydroxides and the basic ion- exchange polymers.
  • the catalyst, the hydrogen donor and the organic solvent may be selected as described above.
  • standard workup procedures such as filtration, extraction and solvent evaporation, provide the crude product of Formula III, which may be used without further purification.
  • the isolated product of Formula III may be optionally obtained through chromatography or crystallization from suitable solvents, according to the relevant prior art methods.
  • the process of the present invention describes the previously undisclosed preparation of key intermediates of ezetimibe through an improved Asymmetric Transfer Hydrogenation protocol.
  • 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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation de composés utiles en tant qu'intermédiaires pour la production d'ézétimibe.
PCT/EP2013/002848 2013-09-23 2013-09-23 Nouveau procédé de préparation d'intermédiaires d'ézétimibe WO2015039675A1 (fr)

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PCT/EP2013/002848 WO2015039675A1 (fr) 2013-09-23 2013-09-23 Nouveau procédé de préparation d'intermédiaires d'ézétimibe

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Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0720599A1 (fr) 1993-09-21 1996-07-10 Schering Corporation Composes d'azetidinone hydroxy-substitues efficaces en tant qu'agents hypocholesterolemiques
EP0906278A1 (fr) 1996-05-31 1999-04-07 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
WO2005049592A1 (fr) 2003-11-24 2005-06-02 Hetero Drugs Limited Nouveau procede de preparation d'intermediaire d'ezetimibe
WO2005113495A1 (fr) 2004-05-21 2005-12-01 Sanofi-Aventis Deutschland Gmbh Prodede de production de derives de diphenylazetidinone
WO2007017705A1 (fr) 2005-08-09 2007-02-15 Glenmark Pharmaceuticals Limited Procede de preparation d'azetidinones
WO2007030721A2 (fr) 2005-09-08 2007-03-15 Teva Pharmaceutical Industries Ltd. Procedes pour preparer (3r,4s)-4-((4-benzyloxy)phenyle)-1-(4-fluorophenyle)-3-((s)-3-(4-fluorophenyle)-3-hydroxypropyle)-2-azetidinone, un intermediaire pour la synthese de l'ezetimibe
WO2007120824A2 (fr) 2006-04-10 2007-10-25 Teva Pharmaceutical Industries Ltd. Procédés de synthèse de l'azétidinone
WO2007144780A2 (fr) 2006-03-29 2007-12-21 Medichem S.A. Procédés de synthèse d'ézétimibe et composés intermédiaires pouvant être employés dans sa synthèse
WO2008089984A2 (fr) 2007-01-24 2008-07-31 Krka Procédé de fabrication de l'ézétimibe et de ses dérivés
EP1953140A1 (fr) 2007-01-24 2008-08-06 Krka Procédé pour la préparation d'ézétimibe et ses dérivés
EP1988071A1 (fr) 2006-02-16 2008-11-05 Kotobuki Pharmaceutical Co., Ltd. Méthode de synthèse d'un alcool optiquement actif
WO2010025085A2 (fr) 2008-08-29 2010-03-04 Codexis, Inc. Polypeptides de cetoreductase pour la production stéréosélective de (4s)-3[(5s)-5(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one
WO2010113175A2 (fr) 2009-04-01 2010-10-07 Matrix Laboratories Ltd Procédé enzymatique pour la préparation de la (s)-5-(4-fluorophényl)-5-hydroxy-1-morpholin-4-yl-pentan-1-one, un intermédiaire de l'ézétimibe et la conversion ultérieure en ézétimibe

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0720599A1 (fr) 1993-09-21 1996-07-10 Schering Corporation Composes d'azetidinone hydroxy-substitues efficaces en tant qu'agents hypocholesterolemiques
EP0906278A1 (fr) 1996-05-31 1999-04-07 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
EP1137634A1 (fr) 1998-12-07 2001-10-04 Schering Corporation Procede relatif a la synthese d'azetidinones
WO2005049592A1 (fr) 2003-11-24 2005-06-02 Hetero Drugs Limited Nouveau procede de preparation d'intermediaire d'ezetimibe
US20070149501A1 (en) * 2004-05-21 2007-06-28 Sanofi-Aventis Deutschland Gmbh Process for the preparation of diphenyl azetidinone derivatives
WO2005113495A1 (fr) 2004-05-21 2005-12-01 Sanofi-Aventis Deutschland Gmbh Prodede de production de derives de diphenylazetidinone
WO2007017705A1 (fr) 2005-08-09 2007-02-15 Glenmark Pharmaceuticals Limited Procede de preparation d'azetidinones
WO2007030721A2 (fr) 2005-09-08 2007-03-15 Teva Pharmaceutical Industries Ltd. Procedes pour preparer (3r,4s)-4-((4-benzyloxy)phenyle)-1-(4-fluorophenyle)-3-((s)-3-(4-fluorophenyle)-3-hydroxypropyle)-2-azetidinone, un intermediaire pour la synthese de l'ezetimibe
EP1988071A1 (fr) 2006-02-16 2008-11-05 Kotobuki Pharmaceutical Co., Ltd. Méthode de synthèse d'un alcool optiquement actif
WO2007144780A2 (fr) 2006-03-29 2007-12-21 Medichem S.A. Procédés de synthèse d'ézétimibe et composés intermédiaires pouvant être employés dans sa synthèse
WO2007120824A2 (fr) 2006-04-10 2007-10-25 Teva Pharmaceutical Industries Ltd. Procédés de synthèse de l'azétidinone
WO2008089984A2 (fr) 2007-01-24 2008-07-31 Krka Procédé de fabrication de l'ézétimibe et de ses dérivés
EP1953140A1 (fr) 2007-01-24 2008-08-06 Krka Procédé pour la préparation d'ézétimibe et ses dérivés
WO2010025085A2 (fr) 2008-08-29 2010-03-04 Codexis, Inc. Polypeptides de cetoreductase pour la production stéréosélective de (4s)-3[(5s)-5(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one
WO2010113175A2 (fr) 2009-04-01 2010-10-07 Matrix Laboratories Ltd Procédé enzymatique pour la préparation de la (s)-5-(4-fluorophényl)-5-hydroxy-1-morpholin-4-yl-pentan-1-one, un intermédiaire de l'ézétimibe et la conversion ultérieure en ézétimibe

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
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CHEM. EUR. J., vol. 14, 2008, pages 7699
FUJII A ET AL: "RUTHENIUM(II)-CATALYZED ASYMMETRIC TRANSFER HYDROGENATION OF KETONES USING A FORMIC ACID-TRIETHYLAMINE MIXTURE", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, ACS PUBLICATIONS, US, vol. 118, no. 10, 1 January 1996 (1996-01-01), XP001120756, ISSN: 0002-7863, DOI: 10.1021/JA954126L *
J MOL. CAT. A, vol. 357, 2012, pages 133
PLATINUM METALS REV., vol. 54, 2010, pages 3

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