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WO2000039090A1 - Procede de preparation d'acetate de paroxetine et de ses analogues - Google Patents

Procede de preparation d'acetate de paroxetine et de ses analogues Download PDF

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Publication number
WO2000039090A1
WO2000039090A1 PCT/GB1999/004358 GB9904358W WO0039090A1 WO 2000039090 A1 WO2000039090 A1 WO 2000039090A1 GB 9904358 W GB9904358 W GB 9904358W WO 0039090 A1 WO0039090 A1 WO 0039090A1
Authority
WO
WIPO (PCT)
Prior art keywords
paroxetine
compound
solvent
drying
disorders
Prior art date
Application number
PCT/GB1999/004358
Other languages
English (en)
Inventor
Andrew Simon Craig
David Alan Jones
John Man
Original Assignee
Smithkline Beecham Plc
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 Plc filed Critical Smithkline Beecham Plc
Priority to EP99962403A priority Critical patent/EP1178962A1/fr
Priority to JP2000591002A priority patent/JP2002533441A/ja
Priority to AU18763/00A priority patent/AU1876300A/en
Publication of WO2000039090A1 publication Critical patent/WO2000039090A1/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
    • C07D211/08—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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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 fiammability 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 the steps of (i) drying the reaction solvent in which the compound of formula (1) is prepared; and (ii) treating the solution with acetic acid.
  • the reaction solvent for the preparation of paroxetine base by deprotection of an N-protected paroxetine, for example N-methyl paroxetine, by hydrolysis of an intermediate carbamate is toluene or xylene, preferably it is toluene.
  • paroxetine base is prepared by hydrogenolysis of an N-protected paroxetine, such as N-benzyl paroxetine
  • the solvent is typically an alcohol such as methanol, ethanol, propan-2-ol, or n-butanol, or an ester such as ethyl acetate, or a ketone such as acetone, butanone, or isobutylmethyl ketone, or an ether such as tetrahydrofuran.
  • the reaction solvent is suitably dried before the acetic acid treatment, preferably by means of azeotropic distillation or by means of a drying agent such as anhydrous sodium or magnesium sulphate.
  • the solution is concentrated by removal of between 10% and 75% of the solvent.
  • 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 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 acetate (1 g) was dissolved in water (3 ml) with gentle heating. Isobutylmethyl ketone (15 ml) was added and the solution heated at reflux in a Dean and Stark apparatus until as much water as possible had been removed. The solution was then cooled to 0-5 °C and a white crystalline precipitate formed. The solid was collected by filtration, washed with isobutylmethyl ketone and dried to give paroxetine acetate (0.84 g) as a granular white solid.
  • 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.

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

Abstract

La présente invention concerne un nouveau procédé de préparation de composés pharmaceutiquement actifs et de leurs intermédiaires. L'isomère trans (-) de 4-(4'-fluorophényl)-3-(3',4'-méthylènedioxyphénoxyméthyl)-pipéridine (paroxétine) est un composé important présentant les propriétés des médicaments antidépresseur et anti-Parkinson. Ce composé est utilisé en thérapie sous la forme d'un chlorhydrate pour le traitement, entre autres, de la dépression, des troubles obsessionnels impulsifs et de la panique. L'invention concerne un procédé de préparation d'acétate de paroxétine et de ses analogues.
PCT/GB1999/004358 1998-12-29 1999-12-22 Procede de preparation d'acetate de paroxetine et de ses analogues WO2000039090A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP99962403A EP1178962A1 (fr) 1998-12-29 1999-12-22 Procede de preparation d'acetate de paroxetine et de ses analogues
JP2000591002A JP2002533441A (ja) 1998-12-29 1999-12-22 酢酸パロキセチンおよびそのアナログの製造法
AU18763/00A AU1876300A (en) 1998-12-29 1999-12-22 Process for the preparation of paroxetine acetate and analogues thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9828767.5 1998-12-29
GBGB9828767.5A GB9828767D0 (en) 1998-12-29 1998-12-29 Novel process

Publications (1)

Publication Number Publication Date
WO2000039090A1 true WO2000039090A1 (fr) 2000-07-06

Family

ID=10845123

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1999/004358 WO2000039090A1 (fr) 1998-12-29 1999-12-22 Procede de preparation d'acetate de paroxetine et de ses analogues

Country Status (5)

Country Link
EP (1) EP1178962A1 (fr)
JP (1) JP2002533441A (fr)
AU (1) AU1876300A (fr)
GB (1) GB9828767D0 (fr)
WO (1) WO2000039090A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6686473B2 (en) 2001-02-21 2004-02-03 Synthon Bct Technologies, Llc Process for the production of paroxetine

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3912743A (en) * 1973-01-30 1975-10-14 Ferrosan As 4-Phenylpiperidine compounds
EP0223403A2 (fr) * 1985-10-25 1987-05-27 Beecham Group Plc Dérivé de pipéridine, sa préparation et son utilisation comme médicament
WO1996024595A1 (fr) * 1995-02-06 1996-08-15 Smithkline Beecham Plc Nouvelles formes de l'hydrochlorure de paroxetine
WO1996036636A1 (fr) * 1995-05-17 1996-11-21 Novo Nordisk A/S Procede de preparation de derives de 4-arylpiperidine
EP0810225A1 (fr) * 1996-05-31 1997-12-03 Asahi Glass Company Ltd. Procédé pour la préparation de paroxetine
WO1998053824A1 (fr) * 1997-05-29 1998-12-03 Smithkline Beecham Corporation Nouveau procede

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3912743A (en) * 1973-01-30 1975-10-14 Ferrosan As 4-Phenylpiperidine compounds
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
EP0223403A2 (fr) * 1985-10-25 1987-05-27 Beecham Group Plc Dérivé de pipéridine, sa préparation et son utilisation comme médicament
WO1996024595A1 (fr) * 1995-02-06 1996-08-15 Smithkline Beecham Plc Nouvelles formes de l'hydrochlorure de paroxetine
WO1996036636A1 (fr) * 1995-05-17 1996-11-21 Novo Nordisk A/S Procede de preparation de derives de 4-arylpiperidine
EP0810225A1 (fr) * 1996-05-31 1997-12-03 Asahi Glass Company Ltd. Procédé pour la préparation de paroxetine
WO1998053824A1 (fr) * 1997-05-29 1998-12-03 Smithkline Beecham Corporation Nouveau procede

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6686473B2 (en) 2001-02-21 2004-02-03 Synthon Bct Technologies, Llc Process for the production of paroxetine

Also Published As

Publication number Publication date
EP1178962A1 (fr) 2002-02-13
AU1876300A (en) 2000-07-31
GB9828767D0 (en) 1999-02-17
JP2002533441A (ja) 2002-10-08

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