WO2000039121A1 - 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 PDFInfo
- Publication number
- WO2000039121A1 WO2000039121A1 PCT/GB1999/004364 GB9904364W WO0039121A1 WO 2000039121 A1 WO2000039121 A1 WO 2000039121A1 GB 9904364 W GB9904364 W GB 9904364W WO 0039121 A1 WO0039121 A1 WO 0039121A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- paroxetine
- solvent
- formula
- solution
- Prior art date
Links
Classifications
-
- 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
- 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
- A61P25/24—Antidepressants
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 treating a solution of the compound of formula (1) with acetic acid and a co-solvent.
- the co-solvent is added to the solution of the compound of formula (1).
- the acetic acid is then added to the solution.
- the co-solvent and acetic acid are mixed together and then added to the solution of the compound of formula (1).
- the co-solvent is selected from ethyl acetate, propan-2-ol, propan-1-ol, acetone, butanone, methylisobutyl ketone and ethanol.
- Ethyl acetate is particularly suitable.
- the solution of the compound of formula (1) is in toluene or tetrahydrofuran.
- 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 base in toluene (5 ml of a 0.42 g/ml solution), which had previously been dried with anhydrous magnesium sulphate, was diluted with propan- 2-ol (20 ml) and seeded with crystalline paroxetine acetate. Acetic acid was added and the solution stirred at approximately 20°C overnight. The resulting solid was collected by filtration to give paroxetine acetate as a white 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 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.
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Drying Of Solid Materials (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99962409A EP1140910A1 (en) | 1998-12-29 | 1999-12-22 | Process for the preparation of an acetate salt of paroxetine or paroxetine analogues |
AU18767/00A AU1876700A (en) | 1998-12-29 | 1999-12-22 | Process for the preparation of an acetate salt of paroxetine or paroxetine analogues |
JP2000591032A JP2002533457A (en) | 1998-12-29 | 1999-12-22 | Method for producing paroxetine acetate or paroxetine analog |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9828779.0A GB9828779D0 (en) | 1998-12-29 | 1998-12-29 | Novel process |
GB9828779.0 | 1998-12-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000039121A1 true WO2000039121A1 (en) | 2000-07-06 |
Family
ID=10845132
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1999/004364 WO2000039121A1 (en) | 1998-12-29 | 1999-12-22 | Process for the preparation of an acetate salt of paroxetine or paroxetine analogues |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1140910A1 (en) |
JP (1) | JP2002533457A (en) |
AU (1) | AU1876700A (en) |
GB (1) | GB9828779D0 (en) |
WO (1) | WO2000039121A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002022609A1 (en) * | 2000-09-14 | 2002-03-21 | Asahi Glass Company, Limited | Process for producing paroxetine salt containing substantially no organic solvent |
Citations (2)
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 |
WO1998056787A1 (en) * | 1997-06-10 | 1998-12-17 | Synthon B.V. | 4-Phenylpiperidine compounds |
-
1998
- 1998-12-29 GB GBGB9828779.0A patent/GB9828779D0/en not_active Ceased
-
1999
- 1999-12-22 EP EP99962409A patent/EP1140910A1/en not_active Withdrawn
- 1999-12-22 WO PCT/GB1999/004364 patent/WO2000039121A1/en not_active Application Discontinuation
- 1999-12-22 AU AU18767/00A patent/AU1876700A/en not_active Abandoned
- 1999-12-22 JP JP2000591032A patent/JP2002533457A/en active Pending
Patent Citations (2)
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 |
WO1998056787A1 (en) * | 1997-06-10 | 1998-12-17 | Synthon B.V. | 4-Phenylpiperidine compounds |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002022609A1 (en) * | 2000-09-14 | 2002-03-21 | Asahi Glass Company, Limited | Process for producing paroxetine salt containing substantially no organic solvent |
Also Published As
Publication number | Publication date |
---|---|
GB9828779D0 (en) | 1999-02-17 |
AU1876700A (en) | 2000-07-31 |
EP1140910A1 (en) | 2001-10-10 |
JP2002533457A (en) | 2002-10-08 |
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