EP1140912A1 - Procede de preparation d'un sel d'acetate de paroxetine ou d'analogues de paroxetine - Google Patents

Procede de preparation d'un sel d'acetate de paroxetine ou d'analogues de paroxetine

Info

Publication number
EP1140912A1
EP1140912A1 EP99962415A EP99962415A EP1140912A1 EP 1140912 A1 EP1140912 A1 EP 1140912A1 EP 99962415 A EP99962415 A EP 99962415A EP 99962415 A EP99962415 A EP 99962415A EP 1140912 A1 EP1140912 A1 EP 1140912A1
Authority
EP
European Patent Office
Prior art keywords
compound
acetic acid
paroxetine
salt
disorders
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99962415A
Other languages
German (de)
English (en)
Inventor
Andrew Simon SmithKline Beecham Pharma. CRAIG
David Alan SmithKline Beecham Pharma. JONES
John SmithKline Beecham Pharmaceuticals MAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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 Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1140912A1 publication Critical patent/EP1140912A1/fr
Withdrawn legal-status Critical Current

Links

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
    • C07D211/08—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor.
  • paroxetine is obtained from a toluene solution via an intermediate aqueous solution of the acetate.
  • solid paroxetine acetate is isolated by addition of an excess of acetic acid and diethyl ether to an ether solution of the free base.
  • diethyl ether is hazardous, particularly in a manufacturing environment, due to its very high flammability and potential for explosive residues, especially during drying procedures. Consequently, manufacturing scale operation would involve expensive precautions and specialised apparatus, adding greatly to operating and capital costs. Furthermore, diethyl ether is not a convenient solvent for the manufacture of paroxetine free base. In the literature, toluene is typically used to manufacture the free base, but a distillation step is required to isolate the base and as a result it is produced in the form of a heavy viscous syrup. This distillation step is an inconvenient additional process and adds further to the production costs.
  • the present invention provides a process for the preparation of an acetate salt of a compound of formula (1):
  • R 1 is a substituted phenyl group, preferably 3,4-methylenedioxyphenyl; the process comprising contacting a solution of the compound of formula (1) with an amine acetic acid salt.
  • the amine acetic acid salt is selected from acetic acid salts of ammonia, alkyl amines, aryl amines, aralkyl amines and heterocyclic amines. More preferably, the amine acetic acid salt is selected from acetic acid salts of ammonia, methylamine, dimethylamine, aniline, benzylamine and pyridine. Most preferably, the amine acetic acid salt is ammonium acetate.
  • the acetate salt may be recrystallised from alcohols, ketones, esters, acetic acid or ethers.
  • Particularly suitable solvents include ethyl acetate, ethanol, propan-1-ol, propan-2-ol, acetone, butanone, and isobutylmethyl ketone, either alone or in combination.
  • the recrystallisation step may include, as required, heating, for example including removal of water using Dean & Stark apparatus, treatment with activated charcoal, silica or similar substances used for the removal of impurities, filtration, concentration, cooling and seeding.
  • the acetate may be isolated as a solid by evaporation, freeze-drying or spray-drying.
  • Spray drying from organic solvents or from mixtures of water with organic solvents are preferred in order to achieve satisfactory drying below the glass point.
  • a preferred procedure is evaporation or spray drying directly onto a solid support, particularly one of use as an excipient for the formation of tablets or capsules.
  • the process of this invention may be used to prepare active compounds described in US-A-3912743 and US-A-4007196, and preferably to prepare paroxetine hemihydrate.
  • solvated, amorphous, or anhydrate products may be isolated according to previously disclosed procedures.
  • Paroxetine acetate may be converted to the hydrochloride salt and most preferably 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.
  • Paroxetine is the (-)-trans isomer of 4-(4'-fluorophenyl)-3-(3",4"-methylenedioxy- phenoxymethyl)piperidine.
  • optical resolution may be carried out prior to coupling with the phenol.
  • resolution may be carried out at other stages, such as after deprotection of the piperidine nitrogen.
  • the Reference Example describes two suitable methods of resolution of the N-deprotected compound.
  • 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:
  • compositions for treatment or prophylaxis of the Disorders comprising paroxetine or paroxetine hydrochloride obtained using the process of this invention and a pharmaceutically acceptable carrier,
  • paroxetine or paroxetine hydrochloride 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 hydrochloride obtained using the process of this invention to a person suffering from one or more of the disorders.
  • paroxetine acetate Preparation of paroxetine acetate using ammonium acetate.
  • the product of the reaction, crystalline paroxetine acetate was isolated by filtration. washed with tetrahydrofuran and dried under vacuum.
  • paroxetine acetate 0.5 g
  • propan-2-ol 5 ml
  • the resulting solution was cooled to 0-5°C for 2 hours resulting in the formation of a white precipitate.
  • the solid was collected by filtration, washed with propan-2-ol (1 ml) and dried in vacuo over phosphorous pentoxide to give paroxetine acetate.
  • Paroxetine acetate was also recrystallised from propan-1-ol, acetone, butanone, and isobutylmethyl ketone by analogous procedures.
  • Paroxetine free base is liberated from the (-) trans 4-(4'-fiuoro-phenyl)-3- (3",4"-methylenedioxyphenoxymethyl)piperidine di-p-toluoyl or dibenzoyl tartrate salt by stirring in a mixture of toluene and dilute aqueous sodium hydroxide. The phases are separated and the toluene phase washed with water. Concentrated aqueous hydrochloric acid is then added and the crystalline precipitate collected by filtration and dried.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Child & Adolescent Psychology (AREA)
  • Reproductive Health (AREA)
  • Dermatology (AREA)
  • Nutrition Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention a trait à un nouveau procédé de préparation d'un sel d'acétate d'un composé représenté par la formule (1), dans laquelle R1 est un groupe phényle substitué, de préférence du 3,4-méthylènedioxyphényle; le procédé comporte les étapes consistant à mettre en contact une solution du composé représenté par la formule (1) avec un sel d'acide acétique aminé. L'isomère trans (-) de 4-(4'-fluorophényle)-3-(3',4'méthylènedioxyphénoxyméthyle)-pipéridine (paroxétine) est un composé important possédant des propriétés d'antidépresseur et anti-Parkinson. Ce composé est utilisé en thérapie comme un sel de chlorhydrate pour traiter entre autres la dépression, les troubles compulsifs obsessionnels (OCD) et la panique.
EP99962415A 1998-12-29 1999-12-22 Procede de preparation d'un sel d'acetate de paroxetine ou d'analogues de paroxetine Withdrawn EP1140912A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9828781.6A GB9828781D0 (en) 1998-12-29 1998-12-29 Novel process
GB9828781 1998-12-29
PCT/GB1999/004370 WO2000039123A1 (fr) 1998-12-29 1999-12-22 Procede de preparation d'un sel d'acetate de paroxetine ou d'analogues de paroxetine

Publications (1)

Publication Number Publication Date
EP1140912A1 true EP1140912A1 (fr) 2001-10-10

Family

ID=10845134

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99962415A Withdrawn EP1140912A1 (fr) 1998-12-29 1999-12-22 Procede de preparation d'un sel d'acetate de paroxetine ou d'analogues de paroxetine

Country Status (5)

Country Link
EP (1) EP1140912A1 (fr)
JP (1) JP2002533459A (fr)
AU (1) AU1877300A (fr)
GB (1) GB9828781D0 (fr)
WO (1) WO2000039123A1 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3688827T2 (de) * 1985-10-25 1994-03-31 Beecham Group Plc Piperidinderivat, seine Herstellung und seine Verwendung als Arzneimittel.
EP1078925A1 (fr) * 1997-06-10 2001-02-28 Synthon B.V. Composés 4-phenylpiperidine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0039123A1 *

Also Published As

Publication number Publication date
GB9828781D0 (en) 1999-02-17
WO2000039123A1 (fr) 2000-07-06
AU1877300A (en) 2000-07-31
JP2002533459A (ja) 2002-10-08

Similar Documents

Publication Publication Date Title
BG61323B2 (bg) Производни на пиперидина,тяхното получаване и използването им като лекарства
EP0828735A1 (fr) Procede de preparation de derives de 4-arylpiperidine
AU698637B2 (en) Crystallisation of levobupivacaine and analogues thereof
EP1578738B1 (fr) Hydrobromure d'escitalopram et son procede de preparation
US6489347B1 (en) Process
WO2002006275A1 (fr) Nouveaux procedes de preparation de derives 4-phenylpiperidine
WO2000035873A1 (fr) Procede de preparation de maleate de paroxetine
EP1137646A1 (fr) Derive paroxetinique
EP1140912A1 (fr) Procede de preparation d'un sel d'acetate de paroxetine ou d'analogues de paroxetine
JP2002531451A (ja) パロキセチン塩酸塩の製法
EP1187830A1 (fr) Procede de preparation de paroxetine et composes structurellement apparentes
WO2000039121A1 (fr) Procede de preparation d'un acetate de paroxetine ou d'analogues de paroxetine
EP1178962A1 (fr) Procede de preparation d'acetate de paroxetine et de ses analogues
WO2001029031A1 (fr) Procede de preparation de paroxetine
EP1140911A1 (fr) Procede de preparation d'un acetate de paroxetine et de ses analogues
WO1999032484A1 (fr) Procede de preparation d'hydrochlorure de paroxetine
WO2001014335A1 (fr) Procede de preparation d'un intermediaire de paroxetine
WO2001002346A1 (fr) Diastereomeres cristallins simples d'esters de 2-cyano-3-arylglutarate
US20010008940A1 (en) Novel process
JP2011506526A (ja) ピリド［２，１−ａ］イソキノリン誘導体の製造方法
WO2001002357A2 (fr) Nouveau procede de preparation
WO2001029002A1 (fr) Preparation d'esters de 4-(fluorophenyl)piperidine
WO2000078752A1 (fr) Procede de production de chlorhydrate de paroxetine
WO2001012623A1 (fr) Procede de preparation d'hydrochlorure de paroxetine anhydre
CZ20003343A3 (cs) Krystalická forma paroxetinu

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010618

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20030701