EP1137636A1 - Procede de preparation de maleate de paroxetine - Google Patents

Procede de preparation de maleate de paroxetine

Info

Publication number
EP1137636A1
EP1137636A1 EP99963631A EP99963631A EP1137636A1 EP 1137636 A1 EP1137636 A1 EP 1137636A1 EP 99963631 A EP99963631 A EP 99963631A EP 99963631 A EP99963631 A EP 99963631A EP 1137636 A1 EP1137636 A1 EP 1137636A1
Authority
EP
European Patent Office
Prior art keywords
paroxetine
trans
piperidin
methylendioxyphenoxymethyl
butan
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Withdrawn
Application number
EP99963631A
Other languages
German (de)
English (en)
Inventor
D. A. SmithKline Beecham Pharm. JONES
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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 Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1137636A1 publication Critical patent/EP1137636A1/fr
Withdrawn legal-status Critical Current

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
    • 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.

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)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Ce procédé de préparation d'un maléate de paroxétine, sensiblement dépourvu d'acide 2-[(3S,4R)-trans-4-(4'-fluorophényl)-3-(3'',4''-méthylènedioxyphénoxyméthyl)pipéridin-1-yl]butan-1,4-dioïque, consiste à faire réagir une base libre paroxétine avec de l'acide maléique, à une gamme de températures inférieures à 40 °C, ou à utiliser un alcanol ou une cétone en tant que solvant de réaction, ou un alcanol, un hydrocarbure, une cétone ou un ester en tant que solvant de recristallisation, ou à combiner des températures et solvants appropriés.
EP99963631A 1998-12-11 1999-12-10 Procede de preparation de maleate de paroxetine Withdrawn EP1137636A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9827387.3A GB9827387D0 (en) 1998-12-11 1998-12-11 Novel process
GB9827387 1998-12-11
PCT/GB1999/004175 WO2000035873A1 (fr) 1998-12-11 1999-12-10 Procede de preparation de maleate de paroxetine

Publications (1)

Publication Number Publication Date
EP1137636A1 true EP1137636A1 (fr) 2001-10-04

Family

ID=10844113

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99963631A Withdrawn EP1137636A1 (fr) 1998-12-11 1999-12-10 Procede de preparation de maleate de paroxetine

Country Status (5)

Country Link
EP (1) EP1137636A1 (fr)
JP (1) JP2002532470A (fr)
AU (1) AU1987400A (fr)
GB (1) GB9827387D0 (fr)
WO (1) WO2000035873A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002053540A1 (fr) 2000-12-29 2002-07-11 Pfizer Limited Derive aspartate de l'amlodipine utilise comme antagoniste des canaux calciques
EP1309557B9 (fr) 2000-12-29 2006-11-15 Pfizer Limited Amlodipine hemimaleate
CA2433193C (fr) 2000-12-29 2006-01-31 Pfizer Limited Derive d'amide d'amlodipine
US7335380B2 (en) 2000-12-29 2008-02-26 Synthon Ip Inc. Amlodipine free base
AT5874U1 (de) 2000-12-29 2003-01-27 Bioorg Bv Pharmazeutische zubereitungen enthaltend amlodipinmaleat
EP1309556B1 (fr) 2000-12-29 2004-11-24 Pfizer Limited Fumarate d'amlodipine
WO2002054062A2 (fr) 2000-12-29 2002-07-11 Pfizer Limited Standards de reference destines a la determination de la purete ou de la stabilite de maleate d'amlodipine et procedes correspondants
PL362660A1 (en) 2000-12-29 2004-11-02 Pfizer Limited Process for making amlodipine maleate
MXPA03005882A (es) 2000-12-29 2005-04-19 Pfizer Ltd Derivado amida de amlodipina.
US6653481B2 (en) 2000-12-29 2003-11-25 Synthon Bv Process for making amlodipine
CN110294692B (zh) * 2019-07-26 2020-09-01 河北兰升生物科技有限公司 一种改进的顺式-对位取代的环己基氨基腈马来酸盐的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1422263A (en) * 1973-01-30 1976-01-21 Ferrosan As 4-phenyl-piperidine compounds
EP0223403B1 (fr) * 1985-10-25 1993-08-04 Beecham Group Plc Dérivé de pipéridine, sa préparation et son utilisation comme médicament
EA200001050A1 (ru) * 1998-04-09 2001-04-23 Смитклайн Бичам Плс Малеат пароксетина
ES2138937B1 (es) * 1998-07-07 2000-10-01 Medichem Sa Polimorfo de maleato de paroxetina y formulaciones farmaceuticas que lo contienen.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0035873A1 *

Also Published As

Publication number Publication date
JP2002532470A (ja) 2002-10-02
GB9827387D0 (en) 1999-02-03
WO2000035873A1 (fr) 2000-06-22
AU1987400A (en) 2000-07-03

Similar Documents

Publication Publication Date Title
KR100543614B1 (ko) 4-페닐피페리딘 화합물
US6080759A (en) Paroxetine hydrochloride form A
EP1414454A1 (fr) Glycyrrhyzinate de paroxetine
CA2782862A1 (fr) Formes polymorphes de chlorhydrate de 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazine
EP1137636A1 (fr) Procede de preparation de maleate de paroxetine
EP1137646A1 (fr) Derive paroxetinique
EP1073652A1 (fr) Maleate de paroxetine
EP1155016A1 (fr) Processus de production de solvate acetonique d'hydrochlorure de paroxetine
EP1135383B1 (fr) Solvates de paroxetine propan-2-ol melanges
EP2072510A1 (fr) Forme cristalline d'azélastine
WO2000078752A1 (fr) Procede de production de chlorhydrate de paroxetine
WO2001012623A1 (fr) Procede de preparation d'hydrochlorure de paroxetine anhydre
EP1133492A1 (fr) Procede de fabrication d'hydrochlorure de paroxetine
WO2001025201A1 (fr) Procede de preparation de produit intermediaire de paroxetine
WO1999055699A1 (fr) 10-camphosulfonate de paroxetine pour le traitement des troubles du systeme nerveux central
WO2001014369A2 (fr) Nouveau procede
WO2001025202A1 (fr) Procede de preparation d'intermediaire de la paroxetine
WO2001025230A1 (fr) Procede de preparation de solvate acetonique d'hydrochlorure de paroxetine
US20010008940A1 (en) Novel process
WO2000032596A1 (fr) Sels amines de paroxetine
WO2001025231A1 (fr) Preparation d'un solvate cetonique de chlorhydrate de paroxetine
WO2001029002A1 (fr) Preparation d'esters de 4-(fluorophenyl)piperidine
HK1091806A1 (zh) 抗组胺哌啶生物及制备其的中间体
EP1412350A1 (fr) Sel d'isethionate de paroxetine, procede de preparation et utilisation dans le traitement de la depression
MXPA00010435A (en) Paroxetine 10-camphorsulfonate for treatment of cns disorders

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: 20010601

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

17Q First examination report despatched

Effective date: 20021008

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: 20030219