WO2001014335A1 - Procede de preparation d'un intermediaire de paroxetine - Google Patents

Procede de preparation d'un intermediaire de paroxetine Download PDF

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Publication number
WO2001014335A1
WO2001014335A1 PCT/EP2000/008177 EP0008177W WO0114335A1 WO 2001014335 A1 WO2001014335 A1 WO 2001014335A1 EP 0008177 W EP0008177 W EP 0008177W WO 0114335 A1 WO0114335 A1 WO 0114335A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzyl
paroxetine
fluorophenyl
piperidine
trans
Prior art date
Application number
PCT/EP2000/008177
Other languages
English (en)
Inventor
David Crowe
David Alan Jones
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 AU72789/00A priority Critical patent/AU7278900A/en
Publication of WO2001014335A1 publication Critical patent/WO2001014335A1/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
    • C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—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 two 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 directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor.
  • paroxetine is prepared from an intermediate imide of formula (1), which is reduced to a piperidine (2) and subsequently converted to paroxetine by known means.
  • the present invention provides as novel compounds, trans-piperidinediones of formula (1) above, where R is a benzyl group and R' is an optionally substituted Cj.g-alkyl, aryl-Cj.g-alkyl, Ci .g-allyl or aryl group, and in particular trans- l-benzyl-4-(4'-fluorophenyl)-3-ethoxycarbonylpiperidin-2,6-dione, and trans-l-benzyl-4-(4'-fluorophenyl)-3-methoxycarbonylpiperidin-2,6-dione.
  • N-benzylamidomalonates of structure (4) where R is a benzyl group may be prepared by the reaction of an alkyl malonyl chloride, for example methyl malonylchloride, with benzylamine under basic conditions.
  • a dialkylmalonate ester may be reacted with benzylamine, with or without an auxiliary solvent, preferably by heating benzylamine in excess malonate ester as solvent.
  • the imide product (1) in which R is methyl is mainly the trans isomer, but can contain as much as 5% of the cis isomer.
  • the imide product (1), in which R is benzyl when prepared by the processes of this invention, contains very much lower levels of cis isomer, for example less than 0.5%, preferably less than 0.1%.
  • Paroxetine may be prepared from the compounds of structure (1) of this invention by reduction to the carbinol (2) as described in US 4,902,801, followed by activation, reaction with sesamol, and removal of the benzyl group.
  • the N-benzyl imides of structure (1) may be reduced to N-benzyl piperidine carbinols of structure (2) by means of a hydride reducing reagent, such as lithium aluminiumhydride or sodium borohydride, in a suitable solvent, for example tetrahydrofuran.
  • a hydride reducing reagent such as lithium aluminiumhydride or sodium borohydride
  • a suitable solvent for example tetrahydrofuran.
  • the coupling is preferably carried out via formation of a sulphonate such as 4-(4-fluorophenyl)-3-methylsulfonyloxymethyl- 1 - benzylpiperidine and reaction with sesamol under basic conditions.
  • Paroxetine is the (-)-trans isomer of 4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl) piperidine, so the preparation of paroxetine from (2) requires a resolution step.
  • the carbinol (2) is resolved into (+) and (-) enantiomers and the (-) isomer is coupled with sesamol.
  • the resolution of (2) may be carried out using a chiral acid to form diastereomeric salts which are separated by crystallisation.
  • Prefered chiral acids are ditoluoyltartaric acid or dibenzoyltartaric acid.
  • the resolution may be achieved at the later stages of the synthesis, for example ( ⁇ ) paroxetine may be resolved using L(-)-di-p-toluoyl tartaric acid.
  • paroxetine via a carbinol of structure (2) requires the removal of the N-benzyl protecting group from N-benzyl paroxetine.
  • nitrogen deprotection via an intermediate carbamate as described for demethylation in US 4,902,801 may also be used for N-benzyl deprotection, and that this process can be operated under surprisingly mild conditions.
  • elevated temperatures are preferred for the reaction of N-methylparoxetine with phenyl chloro formate
  • ambient or sub-ambient temperatures are sufficient for the efficient reaction of N-benzyl paroxetine with phenyl chloroformate.
  • the resultant paroxetine is preferably obtained as or converted to a pharmaceutically acceptable derivative such as a salt, more especially the methanesulphonate salt or the hydrochloride salt and most preferably the hemihydrate of that salt, as described in EP- A-0223403.
  • Paroxetine free base may be converted to paroxetine methanesulphonate by treatment with methansulphonic acid or a labile derivative thereof, for example a soluble salt such as ammonium methanesulphonate.
  • Paroxetine hydrochloride may be prepared by treatment of paroxetine free base with a source of hydrogen chloride, for example gaseous hydrogen chloride, or a solution thereof, or aqueous hydrochloric acid.
  • paroxetine hydrochloride by removal of an N-benzyl group from N- benzyl substituted paroxetine free base by catalytic hydrogenolysis followed by treatment with a source of hydrogen chloride has been described in PCT WO 98/01424 (see Example 22) and PCT WO 98/53424 (see Example 7).
  • N-benzyl group can be carried out by hydrogenation of a salt of N-benzyl paroxetine resulting in the preparation of the correspondingparoxetme salt, such as the hydrochloride, whereby a separate salt forming step is avoided.
  • a salt of N-benzyl paroxetine resulting in the preparation of the correspondingparoxetme salt, such as the hydrochloride
  • a separate salt forming step is avoided.
  • Such a process is described in Examples 18 and 23 of WO 98/01424 in which is disclosed the direct preparation of paroxetine hydrochloride hemihydrate (7) by catalytic hydrogenation of (-)-trans-l-benzyl-4-(4-fluorophenyl)-3-(3 ,4- methylenedioxyphenoxymethyl) piperidine hydrochloride (8) in propan-2-ol.
  • paroxetine hydrochloride is prepared from (-)-trans-l- benzyl-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl) piperidine hydrochloride by catalytic hydrogenation in either
  • a mixture of propan-2-ol and a co-solvent such as water or acetic acid, optionally in the presence of water, or an alternative solvent, preferably ethanol or methanol, optionally with a co-solvent such as water or acetic acid, or a mixture thereof.
  • Suitable catalysts for the hydrogenation include palladium on an inert support, preferably carbon.
  • the hydrogenation may be carried out at atmospheric or above atmospheric pressure, preferably at elevated temperature, suitably at 50-80°C.
  • the reaction mixture is filtered to remove the catalyst, and the paroxetine hydrochloride is recovered from the filtrate by conventional means, such as concentration by evaporation, optionally adding a further solvent to assist crystallisation of the desired product.
  • any of the known crystalline forms of paroxetine hydrochloride may be isolated from the process of this invention, provided suitable conditions are employed at the final isolation step. For example, if water is present during the isolation step, the isolated product is paroxetine hydrochloride hemihydrate. Other anhydrous forms of paroxetine hydrochloride may be isolated using suitable solvent systems, as described in GB 2297550.
  • the present invention includes within its scope the compound paroxetine, particularly paroxetine hydrochloride, especially as an anhydrate or the hemihydrate, when obtained via any aspect of this invention, and any novel intermediates resulting from the described procedures.
  • Paroxetine obtained using this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or WO96/24595, either as solid formulations or as solutions for oral or parenteral use.
  • paroxetine especially paroxetine hydrochloride, obtained using this invention
  • the present invention also provides: a pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine or paroxetine salt obtained using the process of this invention and a pharmaceutically acceptable carrier; the use of paroxetine or paroxetine salt obtained using the process of this invention to manufacture a medicament for the treatment or prophylaxis of the Disorders; and a method of treating the Disorders which comprises administering an effective or prophylactic amount of paroxetine or paroxetine salt obtained using the process of this invention to a person suffering from one or more of the Disorders.
  • Pharmaceutical compositions using active compounds prepared in accordance with this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.
  • the composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to 100 mg, for example 10 to 50 mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferably unit doses contain 20 mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400 mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
  • Preferred unit dosage forms include tablets or capsules, including formulations adapted for controlled or delayed release.
  • compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
  • Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilised in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.

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

Abstract

L'invention concerne un procédé de préparation d'une trans-pipéridinedione représentée par la formule (I), où R désigne un groupe benzyle et R' désigne un groupe alkyle C1-6, alkyl, aryl-C1-6-alkyl, allyle C1-6 ou aryle éventuellement substitué, ledit procédé consistant à faire réagir un ester cinnamate de formule (3), où R'', considéré indépendamment, a la même signification que R', avec un malonamide (4) en présence d'une base forte. Le composé (2) est utilisé dans la préparation de la paroxétine. La préparation de la paroxétine se fait par le biais de la méthode utilisant les composés (3 et 4), ce qui permet d'éviter la formation d'impuretés difficiles à éliminer que l'on obtient suivant les autres méthodes.
PCT/EP2000/008177 1999-08-25 2000-08-18 Procede de preparation d'un intermediaire de paroxetine WO2001014335A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU72789/00A AU7278900A (en) 1999-08-25 2000-08-18 Process for preparation of paroxetin intermediate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9920147.7A GB9920147D0 (en) 1999-08-25 1999-08-25 Novel process
GB9920147.7 1999-08-25

Publications (1)

Publication Number Publication Date
WO2001014335A1 true WO2001014335A1 (fr) 2001-03-01

Family

ID=10859798

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/008177 WO2001014335A1 (fr) 1999-08-25 2000-08-18 Procede de preparation d'un intermediaire de paroxetine

Country Status (3)

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AU (1) AU7278900A (fr)
GB (1) GB9920147D0 (fr)
WO (1) WO2001014335A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1242378A1 (fr) * 1999-12-23 2002-09-25 SmithKline Beecham Corporation Nouveaux procedes
EP1726591A2 (fr) * 2005-05-26 2006-11-29 Apotecnia , S.A. Procedé de la Fabrication de l'Hemihydrate de l'Hydrochlorure de Paroxetine

Citations (3)

* 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
US4902801A (en) * 1985-08-10 1990-02-20 Beecham Group Plc. Process for preparing aryl-piperidine carbinols and novel intermediates used in the process
US5371092A (en) * 1990-11-24 1994-12-06 Beecham Group, P.L.C. Use of paroxetine for the treatment of senile dementia, bulimia, migraine or anorexia

Patent Citations (3)

* 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
US4902801A (en) * 1985-08-10 1990-02-20 Beecham Group Plc. Process for preparing aryl-piperidine carbinols and novel intermediates used in the process
US5371092A (en) * 1990-11-24 1994-12-06 Beecham Group, P.L.C. Use of paroxetine for the treatment of senile dementia, bulimia, migraine or anorexia

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1242378A1 (fr) * 1999-12-23 2002-09-25 SmithKline Beecham Corporation Nouveaux procedes
EP1242378A4 (fr) * 1999-12-23 2003-01-15 Smithkline Beecham Corp Nouveaux procedes
EP1726591A2 (fr) * 2005-05-26 2006-11-29 Apotecnia , S.A. Procedé de la Fabrication de l'Hemihydrate de l'Hydrochlorure de Paroxetine
EP1726591A3 (fr) * 2005-05-26 2007-07-25 Apotecnia , S.A. Procedé de la Fabrication de l'Hemihydrate de l'Hydrochlorure de Paroxetine

Also Published As

Publication number Publication date
GB9920147D0 (en) 1999-10-27
AU7278900A (en) 2001-03-19

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