WO2000035873A1 - Process for preparation of paroxetine maleate - Google Patents

Process for preparation of paroxetine maleate Download PDF

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Publication number
WO2000035873A1
WO2000035873A1 PCT/GB1999/004175 GB9904175W WO0035873A1 WO 2000035873 A1 WO2000035873 A1 WO 2000035873A1 GB 9904175 W GB9904175 W GB 9904175W WO 0035873 A1 WO0035873 A1 WO 0035873A1
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WIPO (PCT)
Prior art keywords
paroxetine
trans
piperidin
methylendioxyphenoxymethyl
butan
Prior art date
Application number
PCT/GB1999/004175
Other languages
French (fr)
Inventor
David Alan Jones
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 AU19874/00A priority Critical patent/AU1987400A/en
Priority to EP99963631A priority patent/EP1137636A1/en
Priority to JP2000588135A priority patent/JP2002532470A/en
Publication of WO2000035873A1 publication Critical patent/WO2000035873A1/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
    • 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
    • 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

Definitions

  • This invention relates to a novel process for preparing a pharmaceutically active compound. More specifically, the invention provides processes for preparing maleate salts of paroxetine free from a structurally similar impurity.
  • a particularly useful salt of paroxetine is the maleate.
  • Example 2 of US 4,007,196 discloses the preparation of paroxetine maleate by crystallisation from ethanol/diethyl ether.
  • Paroxetine maleate is now known to be obtainable both as a salt in which the ratio of paroxetine to maleic acid (by mole) is 1:1 and as a salt in which the ratio of paroxetine to maleic acid (by mole) is 2: 1.
  • the 1 :1 salt has been found to exist in two polymorphic forms, referred to as Form A and Form B.
  • the preparation of the 1 : 1 and 2:1 salts, and the polymorphs, is described in GB 9823856.1.
  • paroxetine maleate may be prepared substantially free of 2-[(3 S,4R)-trans-4-(4'-fluorophenyl)-3-(3 ",4"- methylendioxyphenoxymethyl) piperidin-l-yl]butan-l,4-dioic acid by reaction of paroxetine free base with maleic acid in a temperature range previously considered sub- optimal, or by the selection of suitable solvents for the reaction or recrystallization of the product, or by a combination of suitable temperatures and solvents.
  • the present invention provides a process for preparation of a paroxetine maleate salt substantially free of 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3",4"- methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4-dioic acid, which comprises reacting paroxetine free base with maleic acid in solution at a temperature below 40°C, and crystallising a maleate salt from the solution.
  • This procedure may be used to prepare the 2: 1 salt and 1 : 1 salt by contacting appropriate stoichiometric amounts of the acid and paroxetine free base, and is preferably used with seeding for the preparation of Form B paroxetine 1 : 1 maleate.
  • the present invention provides a process for preparation of a paroxetine maleate salt substantially free of 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3",4"- methylendioxyphenoxymethyl)piperidin- 1 -yl]butan- 1 ,4-dioic acid, which comprises reacting paroxetine free base with maleic acid in solution in an alkanol or ketone solvent and crystallising a maleate salt from the solution.
  • Preferred solvents for the preparation of paroxetine maleate substantially free of 2- [(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3",4"-methylendioxyphenoxymethyl)piperidin-l- yl]butan-l,4-dioic acid are alcohols such as propan-2-ol, or ketones such as methyl isobutylketone or acetone.
  • a particularly suitable solvent is propan-2-ol, especially for the preparation of paroxetine 1 :1 maleate Form A. Reaction of paroxetine and maleic acid in propan-2-ol gives paroxetine maleate Form A even at elevated temperatures with little or no impurity formation.
  • a paroxetine maleate salt containing 2-[(3S,4R)-trans- 4-(4'-fluorophenyl)-3-(3",4"-methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4-dioic acid is purified by crystallisation from an alkanol, or ketone solvent to give a paroxetine maleate containing low levels of impurity.
  • Solvents which can be used for the preparation of substantially pure paroxetine maleate may also be used for the purification of the impure salt by crystallisation. Surprisingly, some solvents which are not preferred for the preparation of pure paroxetine maleate, for example ethyl acetate, may be used successfully for purification.
  • the required polymorphic form of paroxetine 1 :1 maleate may be prepared by seeding with the appropriate seed crystals prior to crystallisation, optionally by recrystallization from a different solvent after purification.
  • Product that is "substantially free" of the 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3",4"- methylendioxyphenoxymethyl)piperidin- 1 -yljbutan- 1 ,4-dioic acid impurity typically contains less than 5% of the impurity. Suitably low levels of the impurity are less than 2%, more preferably less than 1% and optimally less than 0.2%.
  • the paroxetine maleate may obtained as a solvate, when during isolation from solution it becomes associated with the solvent in which it is dissolved. Any such solvate forms a further aspect of this invention.
  • Solvates may be returned to the unsolvated salt by heating, for example by oven-drying, or by treatment with a displacement solvent which does not form a solvate.
  • Paroxetine free base may be prepared according to the procedures generally outlined in US Patent No 4,007,196 and EP-B-0 223403. Maleic acid is commercially available.
  • a paroxetine maleate substantially free of 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3",4"- methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4-dioic acid obtainable by the processes of this invention forms another aspect of this invention, and may be used in therapy as a pharmaceutically acceptable salt of paroxetine.
  • the paroxetine maleate salt substantially free of 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-3- (3",4"-methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4-dioic acid of this invention (hereinafter the “compound of the invention") may be used to treat and prevent the following disorders:
  • PMS Pre-Menstrual Syndrome
  • the present invention further provides a method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a compound of the invention to a sufferer in need thereof.
  • the present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of any one or more of the Disorders which comprises an admixture of a compound of the invention with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a compound of the invention for treating and/or preventing any one or more of the Disorders.
  • the present invention also provides the use of a compound of the invention in the manufacture of a medicament for treating and/or preventing any one or more of the Disorders.
  • the present invention is applied to the treatment of depression, OCD and panic.
  • compositions containing a compound of this invention may be formulated for administration by any route, and examples are oral, sub-lingual, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may, if desired, be designed to give slow release of the paroxetine salt.
  • the medicaments may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • the composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to lOOmg, for example 10 to 50mg such as 10, 12.5, 15, 20, 25, 30 or 40mg by a human patient. Most preferably unit doses contain 20mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
  • Preferred unit dosage forms include tablets or capsules.
  • the compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
  • Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilised in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
  • compositions include those described EP-B-0223403, and US 4,007,196 in which the products of the present invention may be used as the active ingredients.
  • Paroxetine maleate 140 g containing approximately 30% 2-[(3S,4R)-trans-4-(4'- fluorophenyl)-3-(3 " ,4"-methylendioxyphenoxymethyl)piperidin- 1 -yl]butan- 1 ,4-dioic acid was suspended in ethyl acetate (800 ml) and heated at reflux for 30 minutes. The suspension was cooled to a few degrees below reflux temperature and filtered. The residual liquor was cooled slowly to ambient temperature and allowed to crystallise. Ultrasonication was used to increase the rate of crystallisation. The solid product was collected by filtration and dried under vacuum to give paroxetine maleate 1 : 1 Form B (52.55 g).
  • Paroxetine base (0.72 g) in propan-2-ol was treated with maleic acid (0.17 g) at 40-50°C, and the mixture was stirred vigorously.
  • a crystalline solid separated from the solution and was isolated by filtration to give paroxetine maleate 1:1 salt Form A free of 2-[(3S,4R)- trans-4-(4'-fluorophenyl)-3-(3",4"-methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4- dioic acid.
  • paroxetine maleate (2.05 g) substantially free of 2-[(3S,4R)- trans-4-(4'-fluorophenyl)-3-(3 ",4"-methylendioxyphenoxymethyl)piperidin- 1 -yl]butan- 1 ,4- dioic acid.

Abstract

Paroxetine maleate is prepared substantially free of 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3',4'-methylendioxyphenoxymethyl) piperidin-1-yl]butan-1,4-dioic acid by reaction of paroxetine free base with maleic acid at a temperature range below 40 °C, or using an alkanol, or ketone as solvent for the reaction, or an alkanol, hydrocarbon, ketone or ester solvent for recrystallization, or by a combination of suitable temperatures and solvents.

Description

PROCESS FOR PREPARATION OF PAROXETINE MALEATE
This invention relates to a novel process for preparing a pharmaceutically active compound. More specifically, the invention provides processes for preparing maleate salts of paroxetine free from a structurally similar impurity.
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 approved for use in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic.
A particularly useful salt of paroxetine is the maleate. Example 2 of US 4,007,196 discloses the preparation of paroxetine maleate by crystallisation from ethanol/diethyl ether. Paroxetine maleate is now known to be obtainable both as a salt in which the ratio of paroxetine to maleic acid (by mole) is 1:1 and as a salt in which the ratio of paroxetine to maleic acid (by mole) is 2: 1. Also the 1 :1 salt has been found to exist in two polymorphic forms, referred to as Form A and Form B. The preparation of the 1 : 1 and 2:1 salts, and the polymorphs, is described in GB 9823856.1.
It has now been discovered that the known procedures for manufacturing paroxetine maleate give rise to substantial amounts (up to 30%) of an undesirable impurity, 2- [(3 S ,4R)-trans-4-(4'-fiuorophenyl)-3 -(3 " ,4 " -methy lendioxyphenoxymethyl)piperidin- 1 - yl]butan-l ,4-dioic acid, usually in the form of a salt, for example with paroxetine itself. The existence of this impurity is not easy to detect as a result of its chemical similarity to the desired paroxetine salt; it has not previously been mentioned in the literature, and no processes have been described for its prevention or removal.
This invention is based on the finding that paroxetine maleate may be prepared substantially free of 2-[(3 S,4R)-trans-4-(4'-fluorophenyl)-3-(3 ",4"- methylendioxyphenoxymethyl) piperidin-l-yl]butan-l,4-dioic acid by reaction of paroxetine free base with maleic acid in a temperature range previously considered sub- optimal, or by the selection of suitable solvents for the reaction or recrystallization of the product, or by a combination of suitable temperatures and solvents.
Accordingly in one aspect the present invention provides a process for preparation of a paroxetine maleate salt substantially free of 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3",4"- methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4-dioic acid, which comprises reacting paroxetine free base with maleic acid in solution at a temperature below 40°C, and crystallising a maleate salt from the solution.
Hitherto a reaction temperature of above 70°C was thought to be advantageous. The disadvantages of crystallisation at low temperature are overcome by careful control of crystallisation conditions, including the addition of seeds of the desired salt or polymorph.
This procedure may be used to prepare the 2: 1 salt and 1 : 1 salt by contacting appropriate stoichiometric amounts of the acid and paroxetine free base, and is preferably used with seeding for the preparation of Form B paroxetine 1 : 1 maleate.
In another aspect the present invention provides a process for preparation of a paroxetine maleate salt substantially free of 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3",4"- methylendioxyphenoxymethyl)piperidin- 1 -yl]butan- 1 ,4-dioic acid, which comprises reacting paroxetine free base with maleic acid in solution in an alkanol or ketone solvent and crystallising a maleate salt from the solution.
Preferred solvents for the preparation of paroxetine maleate substantially free of 2- [(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3",4"-methylendioxyphenoxymethyl)piperidin-l- yl]butan-l,4-dioic acid are alcohols such as propan-2-ol, or ketones such as methyl isobutylketone or acetone.
A particularly suitable solvent is propan-2-ol, especially for the preparation of paroxetine 1 :1 maleate Form A. Reaction of paroxetine and maleic acid in propan-2-ol gives paroxetine maleate Form A even at elevated temperatures with little or no impurity formation.
In a further aspect of the invention, a paroxetine maleate salt containing 2-[(3S,4R)-trans- 4-(4'-fluorophenyl)-3-(3",4"-methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4-dioic acid is purified by crystallisation from an alkanol, or ketone solvent to give a paroxetine maleate containing low levels of impurity.
Solvents which can be used for the preparation of substantially pure paroxetine maleate may also be used for the purification of the impure salt by crystallisation. Surprisingly, some solvents which are not preferred for the preparation of pure paroxetine maleate, for example ethyl acetate, may be used successfully for purification. The required polymorphic form of paroxetine 1 :1 maleate may be prepared by seeding with the appropriate seed crystals prior to crystallisation, optionally by recrystallization from a different solvent after purification.
Product that is "substantially free" of the 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3",4"- methylendioxyphenoxymethyl)piperidin- 1 -yljbutan- 1 ,4-dioic acid impurity typically contains less than 5% of the impurity. Suitably low levels of the impurity are less than 2%, more preferably less than 1% and optimally less than 0.2%.
The paroxetine maleate may obtained as a solvate, when during isolation from solution it becomes associated with the solvent in which it is dissolved. Any such solvate forms a further aspect of this invention. Solvates may be returned to the unsolvated salt by heating, for example by oven-drying, or by treatment with a displacement solvent which does not form a solvate.
Paroxetine free base may be prepared according to the procedures generally outlined in US Patent No 4,007,196 and EP-B-0 223403. Maleic acid is commercially available.
A paroxetine maleate substantially free of 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3",4"- methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4-dioic acid obtainable by the processes of this invention forms another aspect of this invention, and may be used in therapy as a pharmaceutically acceptable salt of paroxetine.
The paroxetine maleate salt substantially free of 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-3- (3",4"-methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4-dioic acid of this invention, (hereinafter the "compound of the invention") may be used to treat and prevent the following disorders:
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
Substance Abuse
These disorders are hereinafter referred to as "the Disorders". The present invention further provides a method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a compound of the invention to a sufferer in need thereof.
The present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of any one or more of the Disorders which comprises an admixture of a compound of the invention with a pharmaceutically acceptable carrier.
The present invention also provides the use of a compound of the invention for treating and/or preventing any one or more of the Disorders.
The present invention also provides the use of a compound of the invention in the manufacture of a medicament for treating and/or preventing any one or more of the Disorders.
Most suitably the present invention is applied to the treatment of depression, OCD and panic.
Compositions containing a compound of this invention may be formulated for administration by any route, and examples are oral, sub-lingual, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may, if desired, be designed to give slow release of the paroxetine salt.
The medicaments may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
The composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to lOOmg, for example 10 to 50mg such as 10, 12.5, 15, 20, 25, 30 or 40mg by a human patient. Most preferably unit doses contain 20mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
Preferred unit dosage forms include tablets or capsules. The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilised in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
Specific examples of pharmaceutical compositions include those described EP-B-0223403, and US 4,007,196 in which the products of the present invention may be used as the active ingredients.
The following Examples illustrate the present invention.
Example 1
Paroxetine maleate (140 g) containing approximately 30% 2-[(3S,4R)-trans-4-(4'- fluorophenyl)-3-(3 " ,4"-methylendioxyphenoxymethyl)piperidin- 1 -yl]butan- 1 ,4-dioic acid was suspended in ethyl acetate (800 ml) and heated at reflux for 30 minutes. The suspension was cooled to a few degrees below reflux temperature and filtered. The residual liquor was cooled slowly to ambient temperature and allowed to crystallise. Ultrasonication was used to increase the rate of crystallisation. The solid product was collected by filtration and dried under vacuum to give paroxetine maleate 1 : 1 Form B (52.55 g).
Example 2
Paroxetine base (0.72 g) in propan-2-ol was treated with maleic acid (0.17 g) at 40-50°C, and the mixture was stirred vigorously. A crystalline solid separated from the solution and was isolated by filtration to give paroxetine maleate 1:1 salt Form A free of 2-[(3S,4R)- trans-4-(4'-fluorophenyl)-3-(3",4"-methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4- dioic acid.
Example 3
Maleic acid (0.52 g) was added to a rapidly stirred solution of paroxetine in toluene (20 ml) at room temperature. Seed crystals of paroxetine maleate Form A were added and the reaction mixture stirred vigorously. Paroxetine maleate free of 2-[(3S,4R)-trans-4-(4'- fluorophenyl)-3-(3",4"-methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4-dioic acid was isolated by filtration, washed with toluene and dried.
Example 4
A solution of paroxetine base in toluene (2.14 g in 30 ml) was added drop wise to a solution of maleic acid (0.8 g) in propan-2-ol over a 15 minute period. The reaction mixture was stirred vigorously whereupon crystallisation commenced, and the resulting suspension was stirred for 1 hour. The solid was collected by filtration washed with propan-2-ol (5 ml) and dried under vacuum to give paroxetine maleate (2.05 g) substantially free of 2-[(3S,4R)- trans-4-(4'-fluorophenyl)-3-(3 ",4"-methylendioxyphenoxymethyl)piperidin- 1 -yl]butan- 1 ,4- dioic acid.

Claims

1. A process for preparation of a paroxetine maleate salt substantially free of 2- [(3 S ,4R)-trans-4-(4'-fiuorophenyl)-3 -(3 " ,4"-methylendioxyphenoxymethyl)piperidin- 1 - yl]butan-l ,4-dioic acid, which comprises reacting paroxetine free base with maleic acid in solution at a temperature below 40°C, and crystallising a maleate salt from the solution.
2. A process according to claim 1, in which the reaction takes place in an alkanol, ester, hydrocarbon or ketone.
3. A process for preparation of a paroxetine maleate salt substantially free of 2- [(3S,4R)-trans-4-(4'-fluorophenyl)-3-(3",4"-methylendioxyphenoxymethyl)piperidin-l- yl]butan-l,4-dioic acid, which comprises reacting paroxetine free base with maleic acid in solution in an alkanol, or ketone solvent, and crystallising a maleate salt from the solution.
4. A process according to claim 3, in which the reaction takes place at a temperature below 40°C.
5. A process according to any one of claims 1 to 4 in which the solvent is propan-2-ol, toluene, methyl isobutylketone or acetone.
6. A process for obtaining a paroxetine maleate salt substantially free of 2-[(3S,4R)- trans-4-(4'-fluorophenyl)-3-(3",4"-methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4- dioic acid which comprises a) heating a paroxetine maleate salt containing 2-[(3S,4R)- trans-4-(4'-fluorophenyl)-3-(3",4"-methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4- dioic acid in a solvent, b) filtering the hot solution, and c) cooling the solution to induce crystallisation.
7. A process according to claim 6 wherein the solvent is a hydrocarbon, ketone, alkanol or ester solvent.
8. A process according to claim 7 in which the solvent is propan-2-ol, toluene, methyl isobutylketone, acetone or ethyl acetate.
9. A paroxetine maleate salt substantially free of 2-[(3S,4R)-trans-4-(4'-fluorophenyl)-
3-(3",4"-methylendioxyphenoxymethyl)piperidin-l-yl]butan-l,4-dioic acid.
10. A pharmaceutical composition for use in the treatment and/or prevention of any one or more of the Disorders which comprises a compound according to claim 9 or a product of the process of any one of claims 1 to 8, together with a pharmaceutically acceptable carrier.
11. A method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a compound according to claim 9 or a product of the process of any one of claims 1 to 8, to a sufferer in need thereof.
PCT/GB1999/004175 1998-12-11 1999-12-10 Process for preparation of paroxetine maleate WO2000035873A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU19874/00A AU1987400A (en) 1998-12-11 1999-12-10 Process for preparation of paroxetine maleate
EP99963631A EP1137636A1 (en) 1998-12-11 1999-12-10 Process for preparation of paroxetine maleate
JP2000588135A JP2002532470A (en) 1998-12-11 1999-12-10 Preparation of paroxetine maleate

Applications Claiming Priority (2)

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GBGB9827387.3A GB9827387D0 (en) 1998-12-11 1998-12-11 Novel process
GB9827387.3 1998-12-11

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WO (1) WO2000035873A1 (en)

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US6479525B2 (en) 2000-12-29 2002-11-12 Synthon Bv Aspartate derivative of amlodipine
US6518288B2 (en) 2000-12-29 2003-02-11 Synthon Bv Amlodipine fumarate
US6538012B2 (en) 2000-12-29 2003-03-25 Synthon Bv Amlodipine hemimaleate
US6600047B2 (en) 2000-12-29 2003-07-29 Synthon Bv Process for making amlodipine maleate
US6602893B2 (en) 2000-12-29 2003-08-05 Synthon Bv Amide derivative of amlodipine
US6653481B2 (en) 2000-12-29 2003-11-25 Synthon Bv Process for making amlodipine
US6830933B2 (en) 2000-12-29 2004-12-14 Synthon Bv Reference standards for determining the purity or stability of amlodipine maleate and processes therefor
US6919087B2 (en) 2000-12-29 2005-07-19 Synthon Bv Pharmaceutical compositions comprising amlodipine maleate
US7199247B2 (en) 2000-12-29 2007-04-03 Synthon Ip Inc. Amide derivative of amlodipine
US7335380B2 (en) 2000-12-29 2008-02-26 Synthon Ip Inc. Amlodipine free base
EP4006010A4 (en) * 2019-07-26 2022-10-19 Hebei Lansheng Biotech Co., Ltd Improved method for preparing maleate salt of para-substituted cis-cyclohexylamino nitrile

Citations (4)

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US6479525B2 (en) 2000-12-29 2002-11-12 Synthon Bv Aspartate derivative of amlodipine
US6518288B2 (en) 2000-12-29 2003-02-11 Synthon Bv Amlodipine fumarate
US6538012B2 (en) 2000-12-29 2003-03-25 Synthon Bv Amlodipine hemimaleate
US6600047B2 (en) 2000-12-29 2003-07-29 Synthon Bv Process for making amlodipine maleate
US6602893B2 (en) 2000-12-29 2003-08-05 Synthon Bv Amide derivative of amlodipine
US6653481B2 (en) 2000-12-29 2003-11-25 Synthon Bv Process for making amlodipine
US6830933B2 (en) 2000-12-29 2004-12-14 Synthon Bv Reference standards for determining the purity or stability of amlodipine maleate and processes therefor
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US7335380B2 (en) 2000-12-29 2008-02-26 Synthon Ip Inc. Amlodipine free base
EP4006010A4 (en) * 2019-07-26 2022-10-19 Hebei Lansheng Biotech Co., Ltd Improved method for preparing maleate salt of para-substituted cis-cyclohexylamino nitrile

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AU1987400A (en) 2000-07-03
EP1137636A1 (en) 2001-10-04
JP2002532470A (en) 2002-10-02

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