EP1178962A1 - Process for the preparation of paroxetine acetate and analogues thereof - Google Patents
Process for the preparation of paroxetine acetate and analogues thereofInfo
- Publication number
- EP1178962A1 EP1178962A1 EP99962403A EP99962403A EP1178962A1 EP 1178962 A1 EP1178962 A1 EP 1178962A1 EP 99962403 A EP99962403 A EP 99962403A EP 99962403 A EP99962403 A EP 99962403A EP 1178962 A1 EP1178962 A1 EP 1178962A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- paroxetine
- compound
- solvent
- drying
- 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- Withdrawn
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
- 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.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Reproductive Health (AREA)
- Pregnancy & Childbirth (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Hospice & Palliative Care (AREA)
- Gynecology & Obstetrics (AREA)
- Child & Adolescent Psychology (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor. 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. There is described a process for the preparation of paroxetine acetate and analogues thereof.
Description
PROCESS FOR THE PREPARATION OF PAROXETINE ACETATE AND ANALOGUES THEREOF
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 inter 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 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.
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 ) :
in which R1 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.
Typically, 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. When 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. Suitably the solution is concentrated by removal of between 10% and 75% of the solvent.
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-0 152 273, 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.
A mixture of (-)-trans-N-phenoxycarbonyl-4-(4'-fluorophenyl)-3-(3',4'- methylenedioxy-phenoxymethyl)piperidine (5.0 kg) and potassium hydroxide flake (4.5 kg) in toluene (75.0 litres) is heated at reflux under a nitrogen atmosphere for four hours and then the mixture allowed to cool to 20-30°C. Water (50.0 litres) is added and the mixture stirred for 30 minutes and then allowed to settle for 30 minutes. The organic layer is separated, dried with magnesium sulphate (6.0 kg), stirred for 15 minutes and filtered. Seeds of paroxetine acetate (10 g) are added to the filtrate followed by the slow addition of glacial acetic acid (0.7 kg), and the solution is stirred at approximately 20°C for 2 hours. The resulting white crystalline solid is isolated by centrifugation, washed with toluene (10 litres) and dried under vacuum at 40°C for 16 hours.
Preparative Example 2
Preparation of paroxetine acetate from toluene.
Acetic acid (1.6 ml) was added dropwise to a stirred solution of paroxetine base in toluene (8.4 g in 200 ml) which had previously been dried with anhydrous magnesium sulphate. Toluene (100 ml) was removed from the solution by distillation, and the remaining solution cooled to approximately 20°C, seeded with crystalline paroxetine acetate (0J g), and stirred for 1 hour while the product crystallised. The resulting solid was collected by filtration, washed with toluene and dried at 50°C in vacuo for 24 hours to give paroxetine actetate as a white crystalline solid.
Preparative Example 3
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 4
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 J5g) 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:
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'-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.
Claims
A process for the preparation of an acetate salt of a compound of formula (1):
in which R1 is a substituted phenyl group, 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.
2. A process as claimed in Claim 1 wherein the solvent is toluene.
3. A process as claimed in Claim 1 wherein the solvent is 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 tetrahy drofuran..
4. A process as claimed in any one of Claims 1 to 3 wherein the volume of solvent is reduced by between 10% and 75%.
5. A process as claimed in any one of Claims 1 to 3 wherein the solvent is dried by azeotropic distillation or by the use of a drying agent.
6. A process as claimed in any one of Claims 1 to 5 further comprising the step of recrystalhsation from an alcohol, ketone, ester, or ether or from acetic acid; or a mixture thereof.
7. A process as claimed in Claim 6 comprising recrystalhsation 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 6 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.
11. A process as claimed in any preceding claim wherein R is 3 ",4"- methylenedioxyphenyl.
12. A process for preparation of (-)trαrø-4-(4'-fluorophenyl)-3-(3",4"- methylenedioxyphenoxymethyl)piperidine that incorporates the process of any one of claims 1 to 11.
13. (-)trαrø-4-(4'-fluorophenyl)-3 -(3 " ,4" -methylenedioxyphenoxymethyl)- piperidine whenever obtained by a process including the process of any one of claims 1 to 12.
14. (-)trαrø-4-(4'-fluorophenyl)-3-(3",4"-methylenedioxyphenoxymethyl)- 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.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9828767 | 1998-12-29 | ||
GBGB9828767.5A GB9828767D0 (en) | 1998-12-29 | 1998-12-29 | Novel process |
PCT/GB1999/004358 WO2000039090A1 (en) | 1998-12-29 | 1999-12-22 | Process for the preparation of paroxetine acetate and analogues thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1178962A1 true EP1178962A1 (en) | 2002-02-13 |
Family
ID=10845123
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99962403A Withdrawn EP1178962A1 (en) | 1998-12-29 | 1999-12-22 | Process for the preparation of paroxetine acetate and analogues thereof |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1178962A1 (en) |
JP (1) | JP2002533441A (en) |
AU (1) | AU1876300A (en) |
GB (1) | GB9828767D0 (en) |
WO (1) | WO2000039090A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL1017421C2 (en) | 2001-02-21 | 2002-01-15 | Synthon Bv | Process for the production of paroxetine. |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1422263A (en) * | 1973-01-30 | 1976-01-21 | Ferrosan As | 4-phenyl-piperidine compounds |
EP0223403B1 (en) * | 1985-10-25 | 1993-08-04 | Beecham Group Plc | Piperidine derivative, its preparation, and its use as medicament |
SK283608B6 (en) * | 1995-02-06 | 2003-10-07 | Smithkline Beecham Plc | New forms of parotexin hydrochloride |
WO1996036636A1 (en) * | 1995-05-17 | 1996-11-21 | Novo Nordisk A/S | Process for preparing 4-aryl-piperidine derivatives |
JP3882224B2 (en) * | 1996-05-31 | 2007-02-14 | 旭硝子株式会社 | Method for producing paroxetine |
AU7708998A (en) * | 1997-05-29 | 1998-12-30 | Smithkline Beecham Corporation | Novel process |
-
1998
- 1998-12-29 GB GBGB9828767.5A patent/GB9828767D0/en not_active Ceased
-
1999
- 1999-12-22 JP JP2000591002A patent/JP2002533441A/en active Pending
- 1999-12-22 EP EP99962403A patent/EP1178962A1/en not_active Withdrawn
- 1999-12-22 WO PCT/GB1999/004358 patent/WO2000039090A1/en not_active Application Discontinuation
- 1999-12-22 AU AU18763/00A patent/AU1876300A/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO0039090A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO2000039090A1 (en) | 2000-07-06 |
JP2002533441A (en) | 2002-10-08 |
GB9828767D0 (en) | 1999-02-17 |
AU1876300A (en) | 2000-07-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
BG61323B2 (en) | Piperidine derivatives, its preparation and its use as medicaments | |
JPH11505229A (en) | Method for producing 4-aryl-piperidine derivatives | |
NZ501285A (en) | Process for preparing 4-(4'-fluorophenyl)-3-(3', 4'-methylenedioxy-phenyl)-piperidine | |
EP1137646A1 (en) | Derivative of paroxetine | |
JP2002532470A (en) | Preparation of paroxetine maleate | |
EP1178962A1 (en) | Process for the preparation of paroxetine acetate and analogues thereof | |
JP2002531451A (en) | Preparation of paroxetine hydrochloride | |
WO2000039121A1 (en) | Process for the preparation of an acetate salt of paroxetine or paroxetine analogues | |
WO2000039122A1 (en) | Process for the preparation of an acetate salt of paroxetine or paroxetine analogues | |
EP1187830A1 (en) | Process for the preparation of paroxetine and structurally related compounds | |
EP1140912A1 (en) | Process for the preparation of an acetate salt of paroxetine or paroxetine analogues | |
EP1042318A1 (en) | Process for the preparation of paroxetine hydrochloride | |
WO2001014335A1 (en) | Process for preparation of paroxetin intermediate | |
WO1999047519A1 (en) | Crystalline form of paroxetine | |
US20020137938A1 (en) | Novel process | |
EP1242378A1 (en) | Novel processes | |
WO2001029002A1 (en) | Process for the preparation of 4-(fluorophenyl)piperidine esters | |
EP1155016A1 (en) | Process for the production of paroxetine hydrochloride acetone solvate | |
WO2001002346A1 (en) | Crystalline single diastereomers of 2-cyano-3-arylglutarate esters | |
CZ20003343A3 (en) | Crystalline form of paroxetine | |
WO2001012623A1 (en) | Process for the preparation of paroxetine hydrochloride | |
WO2001002357A2 (en) | Process for the synthesis of 4-(4'-fluorophenyl)-piperidines | |
US20010008940A1 (en) | Novel process | |
WO2000078752A1 (en) | Process for the production of paroxetine hydrochloride | |
WO2000032592A1 (en) | Process for the preparation of paroxetine hydrochloride |
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: 20010614 |
|
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 |