WO2001017966A1 - Procede de preparation de 1-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine - Google Patents

Procede de preparation de 1-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine Download PDF

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Publication number
WO2001017966A1
WO2001017966A1 PCT/GB2000/003458 GB0003458W WO0117966A1 WO 2001017966 A1 WO2001017966 A1 WO 2001017966A1 GB 0003458 W GB0003458 W GB 0003458W WO 0117966 A1 WO0117966 A1 WO 0117966A1
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WO
WIPO (PCT)
Prior art keywords
paroxetine
arecoline
process according
compound
formula
Prior art date
Application number
PCT/GB2000/003458
Other languages
English (en)
Inventor
David Crowe
David Alan Jones
Neal Ward
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 AU70258/00A priority Critical patent/AU7025800A/en
Publication of WO2001017966A1 publication Critical patent/WO2001017966A1/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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor.
  • the present invention relates to a new process for the preparation of paroxetine.
  • the improved process of this invention is based on the finding that a mixture of crystalline arecoline hydrobromide in a suitable organic solvent may treated with a suitable anhydrous strongly basic reagent to generate a solution which may be reacted directly with the Grignard reagent.
  • This process is higher yielding than the prior art process, has fewer processing steps, and exposure of operators to the toxic arecoline base is avoided.
  • the hazards associated with handling arecoline hydrobromide which is a non- volatile crystalline solid and freely soluble in water, are greatly reduced.
  • the process of this invention is therefore particularly suitable for large scale manufacture.
  • the present invention provides a process for the preparation of a compound of formula (2) in which a dispersion of crystalline arecoline hydrobromide in an effective organic solvent is treated with an effective anhydrous strongly basic reagent to generate a solution of arecoline free base, which is reacted directly with an organometaUic compound of formula (5)
  • M is a Group II metal and Y is a halogen or the group
  • the compound of formula (5) may a Grignard reagent in which, for example, M is Mg and Y is CI or Br.
  • the compound of formula (5) may also be a symmetric molecule in
  • Suitable effective anhydrous strongly basic reagents are those which react with hydrogen bromide of the arecoline salt to form one or more volatile, inert, or insoluble by-products, and which do not generate water.
  • the process of this invention may be carried out in a number of ways.
  • sodium hydride or a similar reagent is added to arecoline hydrobromide in a suitable organic solvent and the resulting anhydrous solution of arecoline base is used directly in the organometaUic or Grignard reaction.
  • the hydrogen bromide is efficiently removed as inert sodium bromide and volatile hydrogen gas.
  • an inorganic salt such as anhydrous sodium or potassium carbonate may be used. This generates insoluble bromide salts which, together with excess basic reagent may be removed, for example by centrifugation or filtration, to give an anhydrous solution of arecoline free base suitable for reaction with an organometaUic compound or Grignard reagent such as 4-fluorophenyl magnesium bromide.
  • excess Grignard reagent is used as the strong base, for example by reacting arecoline hydrobromide directly with 4-fluorophenyl magnesium bromide firstly to generate the free base, and then to carry out the coupling reaction. This generates inert by-products which do not interfere with the Grignard reaction.
  • solvents are those which are compatible with the organometaUic or Grignard coupling reaction, such as toluene or dichloromethane.
  • a preferred solvent is toluene.
  • Addition of the strongly basic reagent is preferably carried out under an inert atmosphere at ambient or less than ambient temperature.
  • Arecoline hydrobromide is a commercially available compound .
  • the organometalic compounds may be prepared by conventional procedures for such reagents.
  • Compounds of structure (1) may be converted to the active compound paroxetine using conventional procedures disclosed in US-A-3912743 or US-A-4007196, whereby the piperidine ester of structure (2) is reduced to a piperidine carbinol of structure (3), which is coupled with sesamol, then deprotected, to give paroxetine (4).
  • compounds of structure (1) may be resolved to obtain the ⁇ -)trans isomer using conventional reagents such a nitro tartranilic acid, as described in EP-A-0223334 - see Example 5
  • the present invention includes within its scope the compound paroxetine, and paroxetine salts such as 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.
  • 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 and its salts obtained using this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or W096/24595, 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;
  • paroxetine or paroxetine salt obtained using the process of this invention to manufacture a medicament for the treatment or prophylaxis of the Disorders
  • 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.
  • 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. This invention is illustrated by the following Examples.
  • the reaction was quenched by adding 2 hydrochloric acid (250 ml).
  • the aqueous layer was washed with toluene (100 ml) then covered with fresh toluene (100 ml) and adjusted to pH 9-10 by the cautious addition of anhydrous potassium carbonate.
  • the precipitated solids were removed by filtration, the phases were separated and the aqueous phase was extracted twice more with toluene (100 ml).
  • the combined toluene layers were washed with saturated aqueous sodium chloride (100 ml) then evaporated under reduced pressure to give the product as an oil.
  • the aqueous layer was washed with toluene (50 ml) then covered with fresh toluene (50 ml) and adjusted to pH 9-10 by the cautious addition of anhydrous potassium carbonate.
  • the precipitated solids were removed by filtration, the phases were separated and the aqueous phase was extracted twice more with toluene (50 ml).
  • the combined toluene layers were evaporated under reduced pressure to give the product as an oil.
  • reaction was quenched cautiously with 2M hydrochloric acid (50 ml).
  • the aqueous layer was washed with toluene (50 ml) then covered with fresh toluene (50 ml) and adjusted to pH 9-10 by the cautious addition of anhydrous potassium carbonate.
  • the precipitated solids were removed by filtration, the phases were separated and the aqueous phase was extracted twice more with toluene (50 ml).
  • the combined toluene layers were washed with saturated aqueous sodium chloride (100 ml) then evaporated under reduced pressure to give the product as an oil.
  • reaction was quenched cautiously with 2M hydrochloric acid (50 ml).
  • the aqueous layer was washed with toluene (100 ml) then covered with fresh toluene and adjusted to pH 9-10 by the cautious addition of anhydrous potassium carbonate.
  • the precipitated solids were removed by filtration, the phases were separated and the aqueous phase was extracted twice more with toluene (50 ml).
  • the combined toluene layers were washed with saturated brine (50 ml) then evaporated under reduced pressure to give the product as an oil.

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

Abstract

L'invention concerne un composé de formule (2), préparé par traitement d'une dispersion d'hydrobromure d'arécoline cristalline dans un solvant organique avec un réactif anhydre très basique, afin de produire une solution d'une base exempte d'arécoline, cette solution étant mise directement en réaction avec un composé organométallique de formule (5), dans laquelle M est un métal du deuxième groupe et Y est un halogène ou le groupe (I). Le composé de formule (5) est généralement un réactif de Grignard dans lequel M est du Mg et Y est du Cl ou du Br. L'ester de pipéridine de structure (2) est réduit en un carbinol de pipéridine, couplé avec du sésamol, puis déprotégé pour donner de la paroxétine. Ce procédé permet d'éviter la manipulation directe de l'arécoline d'huile alcaloïde irritante.
PCT/GB2000/003458 1999-09-08 2000-09-08 Procede de preparation de 1-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine WO2001017966A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU70258/00A AU7025800A (en) 1999-09-08 2000-09-08 Process for the preparation of 1-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9921243.3A GB9921243D0 (en) 1999-09-08 1999-09-08 Novel process
GB9921243.3 1999-09-08

Publications (1)

Publication Number Publication Date
WO2001017966A1 true WO2001017966A1 (fr) 2001-03-15

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Application Number Title Priority Date Filing Date
PCT/GB2000/003458 WO2001017966A1 (fr) 1999-09-08 2000-09-08 Procede de preparation de 1-methyl-3-carbomethoxy-4-(4'-fluorophenyl)-piperidine

Country Status (3)

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AU (1) AU7025800A (fr)
GB (1) GB9921243D0 (fr)
WO (1) WO2001017966A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7138523B2 (en) 2002-05-16 2006-11-21 Apotex Pharmachem Inc. Preparation of 4-(4-fluorophenyl)-N-alkylnipecotinate esters, 4-(4-fluorophenyl)-N-arylnipecotinate esters and 4-(4-fluorophenyl)-N-aralkylnipecotinate esters

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2546652A (en) * 1949-07-30 1951-03-27 Hoffmann La Roche Pyridindenes and process for their manufacture
WO1999007680A1 (fr) * 1997-08-07 1999-02-18 Brantford Chemicals Inc. Preparation stereoselective de composes piperidine a 4-aryle 3-substitue

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2546652A (en) * 1949-07-30 1951-03-27 Hoffmann La Roche Pyridindenes and process for their manufacture
WO1999007680A1 (fr) * 1997-08-07 1999-02-18 Brantford Chemicals Inc. Preparation stereoselective de composes piperidine a 4-aryle 3-substitue

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ENGELSTOFT M ET AL: "SYNTHESIS AND 5HT MODULATING ACTIVITY OF STEREOISOMERS OF 3-PHENOXYMETHYL-4-PHENYLPIPERIDINES", ACTA CHEMICA SCANDINAVICA,DK,MUNKSGAARD, COPENHAGEN, vol. 50, no. 2, 1996, pages 164 - 169, XP002074608, ISSN: 0904-213X *
KOZIKOWSKI A P ET AL: "CHEMISTRY AND PHARMACOLOGY OF THE PIPERIDINE-BASED ANALOGUES OF COCAINE. IDENTIFICATION OF POTENT DAT INHIBITORS LACKING THE TROPANE SKELETON", JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 41, no. 11, 21 May 1998 (1998-05-21), pages 1962 - 1969, XP002074609, ISSN: 0022-2623 *
WELLER ET AL: "Synthesis of cis- and trans-4a-phenyl- decahydroisoquinolines", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,US,AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, vol. 98, no. 21, 13 October 1976 (1976-10-13), pages 6650 - 6657, XP002080551, ISSN: 0002-7863 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7138523B2 (en) 2002-05-16 2006-11-21 Apotex Pharmachem Inc. Preparation of 4-(4-fluorophenyl)-N-alkylnipecotinate esters, 4-(4-fluorophenyl)-N-arylnipecotinate esters and 4-(4-fluorophenyl)-N-aralkylnipecotinate esters

Also Published As

Publication number Publication date
GB9921243D0 (en) 1999-11-10
AU7025800A (en) 2001-04-10

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