WO2000039123A1 - 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
- WO2000039123A1 WO2000039123A1 PCT/GB1999/004370 GB9904370W WO0039123A1 WO 2000039123 A1 WO2000039123 A1 WO 2000039123A1 GB 9904370 W GB9904370 W GB 9904370W WO 0039123 A1 WO0039123 A1 WO 0039123A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- acetic acid
- paroxetine
- salt
- disorders
- Prior art date
Links
- 0 *OCC(CNCC1)C1c(cc1)ccc1F Chemical compound *OCC(CNCC1)C1c(cc1)ccc1F 0.000 description 1
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)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Child & Adolescent Psychology (AREA)
- Nutrition Science (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000591034A JP2002533459A (ja) | 1998-12-29 | 1999-12-22 | パロキセチン酢酸塩またはパロキセチンアナログの製造方法 |
AU18773/00A AU1877300A (en) | 1998-12-29 | 1999-12-22 | Process for the preparation of an acetate salt of paroxetine or paroxetine analogues |
EP99962415A EP1140912A1 (en) | 1998-12-29 | 1999-12-22 | Process for the preparation of an acetate salt of paroxetine or paroxetine analogues |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9828781.6A GB9828781D0 (en) | 1998-12-29 | 1998-12-29 | Novel process |
GB9828781.6 | 1998-12-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000039123A1 true WO2000039123A1 (en) | 2000-07-06 |
Family
ID=10845134
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1999/004370 WO2000039123A1 (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) | EP1140912A1 (ja) |
JP (1) | JP2002533459A (ja) |
AU (1) | AU1877300A (ja) |
GB (1) | GB9828781D0 (ja) |
WO (1) | WO2000039123A1 (ja) |
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 GBGB9828781.6A patent/GB9828781D0/en not_active Ceased
-
1999
- 1999-12-22 JP JP2000591034A patent/JP2002533459A/ja active Pending
- 1999-12-22 EP EP99962415A patent/EP1140912A1/en not_active Withdrawn
- 1999-12-22 WO PCT/GB1999/004370 patent/WO2000039123A1/en not_active Application Discontinuation
- 1999-12-22 AU AU18773/00A patent/AU1877300A/en not_active Abandoned
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 |
Also Published As
Publication number | Publication date |
---|---|
GB9828781D0 (en) | 1999-02-17 |
EP1140912A1 (en) | 2001-10-10 |
JP2002533459A (ja) | 2002-10-08 |
AU1877300A (en) | 2000-07-31 |
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