WO2000039122A1 - Process for the preparation of an acetate salt of paroxetine or paroxetine analogues - Google Patents

Process for the preparation of an acetate salt of paroxetine or paroxetine analogues Download PDF

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Publication number
WO2000039122A1
WO2000039122A1 PCT/GB1999/004367 GB9904367W WO0039122A1 WO 2000039122 A1 WO2000039122 A1 WO 2000039122A1 GB 9904367 W GB9904367 W GB 9904367W WO 0039122 A1 WO0039122 A1 WO 0039122A1
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Prior art keywords
compound
paroxetine
disorders
piperidine
fluorophenyl
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PCT/GB1999/004367
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French (fr)
Inventor
Andrew Simon Craig
David Alan Jones
John Man
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Smithkline Beecham Plc
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Priority to AU18770/00A priority Critical patent/AU1877000A/en
Priority to JP2000591033A priority patent/JP2002533458A/en
Priority to EP99962412A priority patent/EP1140911A1/en
Publication of WO2000039122A1 publication Critical patent/WO2000039122A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • 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' is a substituted phenyl group, preferably 3,4-methylenedioxyphenyl; the process comprising crystallising the acetate salt from a solvent capable of dehydrating an aqueous solution by forming an azeotrope.
  • the aqueous solution is formed by extracting a solution, typically a toluene solution, of the free base compound of formula (1) with aqueous acetic acid.
  • the aqueous solution is formed by hydrogenolysis of a hot aqueous acetic acid suspension of an N-protected compound of formula (2)
  • R 2 is capable of being removed by hydrogenolysis, preferably a benzyl group.
  • concentration of paroxetine acetate in the aqueous solution can be relatively high (typically about 10-30% w/v).
  • the water can be readily removed, without degradation of the acetate salt, for example, by repeated distillation and replacement with fresh solvent, by means of Dean & Stark apparatus, or a combination of the two techniques.
  • Suitable solvents include methyl isobutyl ketone, propan-2-ol. acetone and toluene, or mixtures of these solvents.
  • 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; and 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.
  • the resulting solution is cooled to 0°C and seeded to initiate crystallisation. After stirring for 2 hours at 0- 10°C, the product is isolated by filtering and drying to give crystalline paroxetine acetate as a fine, white, free-flowing crystalline solid.
  • 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.

Abstract

The present invention relates to a new process for the preparation of an acetate salt of a compound of formula (1), in which R1 is a substituted phenyl group, preferably 3,4-methylenedioxyphenyl; the process comprising crystallising the acetate salt from a solvent capable of dehydrating an aqueous solution by forming an azeotrope. The (-) trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxyphenoxymethyl)-piperidine(paroxetine) is an important compound having antidepressant and anti-Parkinson properties. This compound is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic.

Description

PROCESS FOR THE PREPARATION OF AN ACETATE SALT OF PAROXETINE OR PAROXETINE ANALOGUES
The present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those disclosed is paroxetine, the (-) trans isomer of 4-(4'-fluorophenyl)-3- (3",4"-methylenedioxyphenoxymethyl)piperidine. This compound is used in therapy as the hydrochloride salt to treat ter alia depression, obsessive compulsive disorder (OCD) and panic.
In Example 2 of EP 0 223 403, an earlier application of the present applicant, paroxetine is obtained from a toluene solution via an intermediate aqueous solution of the acetate. In Example 8 of the same disclosure, solid paroxetine acetate is isolated by addition of an excess of acetic acid and diethyl ether to an ether solution of the free base.
The use of 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.
Accordingly, there is a need for a process for the preparation of acetate salts of paroxetine and its analogues which is suitable for large scale manufacture. In its broadest sense, the present invention provides a process for the preparation of an acetate salt of a compound of formula (1):
Figure imgf000004_0001
in which R' is a substituted phenyl group, preferably 3,4-methylenedioxyphenyl; the process comprising crystallising the acetate salt from a solvent capable of dehydrating an aqueous solution by forming an azeotrope.
In one embodiment, the aqueous solution is formed by extracting a solution, typically a toluene solution, of the free base compound of formula (1) with aqueous acetic acid.
In an alternative embodiment, the aqueous solution is formed by hydrogenolysis of a hot aqueous acetic acid suspension of an N-protected compound of formula (2)
Figure imgf000004_0002
wherein R2 is capable of being removed by hydrogenolysis, preferably a benzyl group. The concentration of paroxetine acetate in the aqueous solution can be relatively high (typically about 10-30% w/v). The water can be readily removed, without degradation of the acetate salt, for example, by repeated distillation and replacement with fresh solvent, by means of Dean & Stark apparatus, or a combination of the two techniques. Suitable solvents include methyl isobutyl ketone, propan-2-ol. acetone and toluene, or mixtures of these solvents. Once the water has been removed, the paroxetine acetate can be induced to crystallise by cooling, concentrating, and seeding as necessary.
Following preparation of the acetate salt, it 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.
Alternatively or additionally, 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. As an alternative to isolating the 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. Following the procedure of EP-O 152 273, optical resolution may be carried out prior to coupling with the phenol. Alternatively, 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.
Therapeutic uses of paroxetine, especially paroxetine hydrochloride, obtained using this invention include treatment of: alcoholism, anxiety, depression, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and substance abuse, referred to below as "the Disorders".
Accordingly, the present invention also provides:
a pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine or paroxetine hydrochloride obtained using the process of this invention and a pharmaceutically acceptable carrier,
the use of paroxetine or paroxetine hydrochloride 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 hydrochloride obtained using the process of this invention to a person suffering from one or more of the disorders.
This invention is illustrated by the following Examples.
Examples
Preparative Example 1
Preparation of paroxetine acetate by hydrogenolysis.
A suspension of (-)-trans-l-benzyl-4-(4'-fluorophenyl)-3-((3",4"-methylenedioxy - phenoxymethyl)piperidine (40.9 g, prepared according to the procedure in EP 374674) in acetic acid (12 ml), water (350 ml), and palladium on charcoal catalyst (10%) is heated to 50°C in a pressure hydrogenator and stirred vigorously in a hydrogen atmosphere at 40 p.s.i. When the measured uptake of hydrogen indicates that the reaction is complete, the mixture is cooled, filtered, and mixed with isobutylmethyl ketone (2 litres). The water is removed by refluxing in a Dean and Stark apparatus, and finally by removing half the solvent by distillation. The resulting solution is cooled to 0°C and seeded to initiate crystallisation. After stirring for 2 hours at 0- 10°C, the product is isolated by filtering and drying to give crystalline paroxetine acetate as a fine, white, free-flowing crystalline solid.
Preparative Example 2
Recrystallisation of paroxetine from propan-2-ol
A suspension of paroxetine acetate (0.5 g), in propan-2-ol (5 ml) was heated to reflux with vigorous stirring to dissolve. 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.
Preparative Example 3
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.
Reference Example
Preparation of paroxetine hydrochloride by the resolution of (±) trans 4-(4'- fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)piperidine.
i) (±) trans 4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl) piperidine (1.0 g) was dissolved in methanol (10 ml) and added to a solution of L(-)- di-p-toluoyl tartaric acid (1.25g) in methanol (10 ml). The mixture was seeded and allowed to stand at room temperature and the crystalline product examined by chiral HPLC, using the following system:
Figure imgf000008_0001
Figure imgf000009_0001
Chiral HPLC analysis confirmed that substantially pure (-) trans L(-)-di-p-toluoyl tartrate salt had been isolated. The salt may be further purified by recrystallisation from methanol.
ii) (±) trans 4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl) piperidine (0.50 g) was dissolved in acetonitrile (10 ml) and added to a solution of L-(-)-dibenzoyl tartaric acid (0.65g) in acetonitrile (10 ml). The mixture was seeded and stirred at room temperature. The crystalline product was shown by chiral HPLC to be significantly enriched with the (-) trans dibenzoyl tartrate salt.
iii) Paroxetine free base is liberated from the (-) trans 4-(4'-fluoro-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.

Claims

Claims
A process for the preparation of an acetate salt of a compound of formula (1):
Figure imgf000010_0001
in which R1 is a substituted phenyl group, the process comprising crystallising the acetate salt from a solvent capable of dehydrating an aqueous solution by forming an azeotrope.
2. A process as claimed in Claim 1 wherein the aqueous solution is formed by extracting a solution of the free base compound of formula (1) with aqueous acetic acid.
A process as claimed in Claim 2 wherein the solvent is toluene
4. A process as claimed in Claim 1 wherein the aqueous solution is formed by hydrogenolysis of a hot aqueous acetic acid suspension of an N-protected compound of formula (2)
Figure imgf000011_0001
wherein R2 is capable of being removed by hydrogenolysis.
5. A process as claimed in Claim 4 wherein R2 is a benzyl group.
6. A process as claimed in any one of Claims 1 to 5 further comprising the step of recrystallisation from an alcohol, ketone, ester, or ether or from acetic acid; or a mixture thereof.
7. A process as claimed in Claim 6 comprising recrystallisation from ethyl acetate, ethanol, propan-1-ol, propan-2-ol, acetone, butanone, or isobutylmethyl ketone. or mixture thereof.
8. A process as claimed in any preceding claim further comprising the step of isolation of the solid by evaporation, freeze-drying or spray-drying.
9. A process as claimed in Claim 8 wherein the solid is isolated from an organic solvent; mixture of organic solvents; or mixture of water with one or more organic solvents.
10. A process as Claimed in Claim 8 or Claim 9 wherein the solid is isolated by evaporation or spray drying directly onto a solid support.
1 1. A process as claimed in any preceding claim wherein R is 3\4'- methylenedioxyphenyl.
12. A process for preparation of (-)-trα/M-4-(4'-fluorophenyl)-3-(3"J"- methylenedioxyphenoxymethyl)piperidine that incorporates the process of any one of claims 1 to 1 1.
13. (-)-trαr..s,-4-(4'-fluorophenyl)-3-(3"J"-methylenedioxyphenoxymethyl)- piperidine whenever obtained by a process including the process of any one of claims 1 to 14.
14. (-)-trara-4-(4'-fluorophenyl)-3 -(3 " ,4" -methylenedioxyphenoxymethy 1)- piperidine as claimed in claim 13, in the form of a hydrochloride salt.
15. A pharmaceutical composition for treatment or prophylaxis of the disorders comprising a compound as claimed in claim 13 or 14 and a pharmaceutically acceptable carrier.
16. The use of a compound as claimed in claim 13 or 14 in the manufacture of a medicament for the treatment or prophylaxis of the disorders.
17. A method of treating the disorders which comprises administering an effective or prophylactic amount of a compound as claimed in claim 13 or 14 to a person suffering from one or more of the disorders.
PCT/GB1999/004367 1998-12-29 1999-12-22 Process for the preparation of an acetate salt of paroxetine or paroxetine analogues WO2000039122A1 (en)

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AU18770/00A AU1877000A (en) 1998-12-29 1999-12-22 Process for the preparation of an acetate salt of paroxetine or paroxetine analogues
JP2000591033A JP2002533458A (en) 1998-12-29 1999-12-22 Method for producing paroxetine acetate or paroxetine analog
EP99962412A EP1140911A1 (en) 1998-12-29 1999-12-22 Process for the preparation of an acetate salt of paroxetine or paroxetine analogues

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GB9828780.8 1998-12-29
GBGB9828780.8A GB9828780D0 (en) 1998-12-29 1998-12-29 Novel process

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130172562A1 (en) * 2010-06-17 2013-07-04 Dr. Reddy's Laboratories, Inc. Process for the preparation of a single enantiomer of 3-aminopiperidine dihydrochloride

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0223403A2 (en) * 1985-10-25 1987-05-27 Beecham Group Plc Piperidine derivative, its preparation, and its use as medicament
WO1998001424A1 (en) * 1996-07-08 1998-01-15 Richter Gedeon Vegyészeti Gyár Rt. N-benzylpiperidine and tetrahydropyridine derivatives
WO1998056787A1 (en) * 1997-06-10 1998-12-17 Synthon B.V. 4-Phenylpiperidine compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0223403A2 (en) * 1985-10-25 1987-05-27 Beecham Group Plc Piperidine derivative, its preparation, and its use as medicament
WO1998001424A1 (en) * 1996-07-08 1998-01-15 Richter Gedeon Vegyészeti Gyár Rt. N-benzylpiperidine and tetrahydropyridine derivatives
WO1998056787A1 (en) * 1997-06-10 1998-12-17 Synthon B.V. 4-Phenylpiperidine compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130172562A1 (en) * 2010-06-17 2013-07-04 Dr. Reddy's Laboratories, Inc. Process for the preparation of a single enantiomer of 3-aminopiperidine dihydrochloride

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GB9828780D0 (en) 1999-02-17
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EP1140911A1 (en) 2001-10-10

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