WO2002028834A1 - Procede de preparation de carbonols d'aryl-piperidine et produits intermediaires de ces derniers - Google Patents

Procede de preparation de carbonols d'aryl-piperidine et produits intermediaires de ces derniers Download PDF

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Publication number
WO2002028834A1
WO2002028834A1 PCT/EP2000/009786 EP0009786W WO0228834A1 WO 2002028834 A1 WO2002028834 A1 WO 2002028834A1 EP 0009786 W EP0009786 W EP 0009786W WO 0228834 A1 WO0228834 A1 WO 0228834A1
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WO
WIPO (PCT)
Prior art keywords
compound
process according
hydrogen
paroxetine
aryl
Prior art date
Application number
PCT/EP2000/009786
Other languages
English (en)
Inventor
David Ennis
David Lathbury
Original Assignee
Smithkline Beecham P.L.C.
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 Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to PCT/EP2000/009786 priority Critical patent/WO2002028834A1/fr
Priority to AU2001211337A priority patent/AU2001211337A1/en
Publication of WO2002028834A1 publication Critical patent/WO2002028834A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • the present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor.
  • This invention aims to overcome disadvantages in the existing processes for preparation of such compounds and so to provide alternative processes for their manufacture.
  • This invention has been developed on the basis that compounds of structure (1) below are valuable chemical intermediates useful for the manufacture of important medicinal products, for example paroxetine hydrochloride.
  • paroxetine may be prepared from a compound of structure (1) below in which R is methyl and X is 4-fluoro, that is 4-(4'-fluoropheny ⁇ )-3- hydroxymethyl-1-methylpiperidine, by reaction with 3,4-methylenedioxyphenol followed by demethylation.
  • 4-(4'-fluorophenyl)-3-hydroxymethyl-l -methyl piperidine is prepared by reduction of 4-(4'-fluorophenyl)-3-hydroxymethyl-l -methyl - 1,2,3,6-tetrahydropyridine (II), which is in turn prepared from 4-(4'-fluorophenyl)-l-methyl- 1,2,3,6-tetrahydropyridine (III), by reaction with formaldehyde.
  • compound (II) is prepared by a process in which an -methyl styrene is reacted with formaldehyde and an amine hydrochloride, via compound (III) as an non- isolated intermediate.
  • Known methods for converting compound (III) into compound (II) are inefficient, and the product (II) has been shown to contain approximately 30% residual compound (III). This is carried forward and causes problems with subsequent stages and with residues in the finally intended product.
  • the use of both hydrochloric acid and formaldehyde can give rise to bis-chloromethylether.
  • Paroxetine is the (-) trans isomer of 4-(4'-fluorophenyl)-3-(3',4'- methylenedioxyphenoxymethyl)-piperidine.
  • the above described processes produce compounds of structure (1) as a mixture of enantiomers. Therefore conversion of compounds of structure (1) to useful pharmaceuticals will normally require a resolution stage, as described in EP-A-0223334.
  • This invention provides a process for the preparation of a 4-aryl-3-hydroxymethyl-piperidine of structure (1)
  • R and X are as indicated below, which comprises reducing an isoxazolidine of structure (2).
  • R and R groups may be the same or different hydrogen, alkyl, arylalkyl, allyl, carbonyloxyalkyl, carbonyloxyaryl, or carbonyloxyalkylaryl groups where appropriate to the reactions described below.
  • R is most suitably lower alkyl or allyl.
  • R is most suitably hydrogen for reduction of compounds of structure (2) to compounds of structure (1), but may be a chiral auxiliary when a compound of structure (2) is prepared by an enantioselective synthesis as discussed below.
  • X is one or more of hydrogen, halogen (especially fluoro), hydroxy, alkoxy, nitro, nitrile, amino (optionally protected or substituted), trifluoromethyl, acyl, formyl, carboxyl or carboxyalkyl.
  • alkyl groups are typically lower or C j .g alkyl groups, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl.
  • Aryl groups are typically phenyl and are optionally substituted, for example by nitro, halogen, phenyl or a Cj_ alkyl or alkoxy group.
  • Arylalkyl groups are typically benzyl or substituted benzyl. Conversion of compounds of structure (2) into 3-hydroxymethylpiperidines of structure (1) requires forcing reducing conditions to avoid contamination with intermediate 4-amino-4- aryl-3-hydroxymethylpiperidines of structure (4)
  • Suitable reducing conditions include catalytic transfer hydrogenation with, for example, palladium on charcoal and ammonium formate. Under these conditions the product is exclusively the cis-isomer, but this is not a disadvantage for use as an intermediate in the production of pharmaceutically active ethers such as paroxetine since coupling by displacement of a sulphonyl ester is believed to proceed via a quaternary ammonium cyclic intermediate and results in almost exclusively the trans ether.
  • reduction leading to trans compounds of structure (1) can be achieved with other catalysts.
  • the compounds of structure (2) and the 4-amino-4-aryl-3-hydroxymethylpiperidines of structure (4) that may be obtained as intermediates during reduction of compounds of structure (2) are believed to be novel and form part of this invention.
  • This invention also includes the transformation of compounds of structure (4), obtained by reduction of compounds of structure (2) or by alternative means, to compounds of structure (1).
  • a single enantiomer of the intermediate (2) may be prepared from a chiral precursor, thereby transferring the resolution, normally required after coupling with the aryl moiety, to a very early stage in the overall process.
  • R is as defined above.
  • One suitable reagent for this transformation is the lithium derivative obtained from 4-fluorobromobenzene.
  • Compounds of structure (3) may be resolved by conventional methods to provide a chiral precursor for the subsequent reactions described above.
  • a conventional chiral acid resolving agent may be used, for example dibenzoyl-D-tartaric acid when R is allyl.
  • the compound of structure (3) may be prepared by intramolecular cycloaddition of a nitrile oxide obtained, for example, by oxidation of a 3-(allylamino)-propionaldehyde oxime, which may in turn be prepared by base catalysed addition of an alkyl or arylalkyl substituted allyl amine to acrolein.
  • a compound of structure (1) obtained by processes of this invention may be converted to an active compound disclosed in US-A-4007196 using conventional procedures disclosed therein.
  • paroxetine is preferably obtained as the hydrochloride salt and most preferably as the hemihydrate of that salt, as described in EP-A-0223403.
  • the present invention includes within its scope the compound paroxetine, particularly paroxetine hydrochloride, especially as the hemihydrate, when obtained via any aspect of this invention, and any novel intermediates resulting from the described procedures.
  • Example 1 A solution of acrolein (55 ml) in tetrahydrofuran (50 ml) was added slowly, over 25 minutes, to a solution of diallylamine (90 ml) and DBU (0.88 ml) in tetrahydrofuran (300 ml) at a temperature of approximately -IO C. The mixture was stirred at -15 C for an hour, at which point a solution of sodium hydroxide (30 g) and hydroxylamine hydrochloride (50 g) in water (200 ml) was slowly added over 30 minutes keeping the temperature below 5 C. n-Hexane (300 ml) was added and the reaction allowed to warm up to ambient temperature with stirring.
  • the isoxazolidine product of Example 2 (1.0 g) was dissolved in methanol (80 ml) together with ammonium formate (4.82 g) and heated at reflux for 48 hours with palladium on carbon catalyst (0.5 g). The reaction mixture was filtered through celite and the solvent removed by evaporation at reduced pressure to produce l-allyi-4- 4'- ⁇ luoropnenyl -3- hydroxymethylpiperidine as a yellow oil, 0.59 g (62 %).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de la formule (1). Ce procédé consiste à réduire la formule (2) directement par hydrogénation de transfert catalytique pour supprimer la formation de la formule (4) ou par réduction classique via (4). Le composé (1) est un produit intermédiaire clé pour la paroxétine notamment.
PCT/EP2000/009786 2000-10-06 2000-10-06 Procede de preparation de carbonols d'aryl-piperidine et produits intermediaires de ces derniers WO2002028834A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/EP2000/009786 WO2002028834A1 (fr) 2000-10-06 2000-10-06 Procede de preparation de carbonols d'aryl-piperidine et produits intermediaires de ces derniers
AU2001211337A AU2001211337A1 (en) 2000-10-06 2000-10-06 Process for the preparation of aryl-piperidine carbinols and intermediates thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2000/009786 WO2002028834A1 (fr) 2000-10-06 2000-10-06 Procede de preparation de carbonols d'aryl-piperidine et produits intermediaires de ces derniers

Publications (1)

Publication Number Publication Date
WO2002028834A1 true WO2002028834A1 (fr) 2002-04-11

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AU (1) AU2001211337A1 (fr)
WO (1) WO2002028834A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7199243B2 (en) 2002-11-26 2007-04-03 Pfizer Inc. Piperidine compounds useful as PPAR activators

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
EP0152273A2 (fr) * 1984-02-07 1985-08-21 A/S Ferrosan Dérivé de phénylpipéridine et ses sels, leur préparation, compositions les contenant et leur utilisation thérapeutique
EP0223334A1 (fr) * 1985-08-10 1987-05-27 Beecham Group Plc Procédé de préparation d'aryl-pipéridine-carbinols
EP0300617A1 (fr) * 1987-06-23 1989-01-25 Beecham Group Plc Procédé pour la préparation de carbinols d'arylpipéridine
US5258517A (en) * 1992-08-06 1993-11-02 Sepracor, Inc. Method of preparing optically pure precursors of paroxetine
WO1996036636A1 (fr) * 1995-05-17 1996-11-21 Novo Nordisk A/S Procede de preparation de derives de 4-arylpiperidine
EP0812827A1 (fr) * 1996-06-13 1997-12-17 SUMIKA FINE CHEMICALS Co., Ltd. Dérivés de pipéridine comme intermédiaire pour la production de paroxétine et procédé pour leur préparation
US6153755A (en) * 1996-11-09 2000-11-28 Smithkline Beecham Plc Process for preparing pharmaceutically active compounds and intermediates thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
EP0152273A2 (fr) * 1984-02-07 1985-08-21 A/S Ferrosan Dérivé de phénylpipéridine et ses sels, leur préparation, compositions les contenant et leur utilisation thérapeutique
EP0223334A1 (fr) * 1985-08-10 1987-05-27 Beecham Group Plc Procédé de préparation d'aryl-pipéridine-carbinols
EP0300617A1 (fr) * 1987-06-23 1989-01-25 Beecham Group Plc Procédé pour la préparation de carbinols d'arylpipéridine
US5258517A (en) * 1992-08-06 1993-11-02 Sepracor, Inc. Method of preparing optically pure precursors of paroxetine
WO1996036636A1 (fr) * 1995-05-17 1996-11-21 Novo Nordisk A/S Procede de preparation de derives de 4-arylpiperidine
EP0812827A1 (fr) * 1996-06-13 1997-12-17 SUMIKA FINE CHEMICALS Co., Ltd. Dérivés de pipéridine comme intermédiaire pour la production de paroxétine et procédé pour leur préparation
US6153755A (en) * 1996-11-09 2000-11-28 Smithkline Beecham Plc Process for preparing pharmaceutically active compounds and intermediates thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7199243B2 (en) 2002-11-26 2007-04-03 Pfizer Inc. Piperidine compounds useful as PPAR activators

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AU2001211337A1 (en) 2002-04-15

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