WO2001002357A2 - Nouveau procede de preparation - Google Patents

Nouveau procede de preparation Download PDF

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Publication number
WO2001002357A2
WO2001002357A2 PCT/GB2000/002539 GB0002539W WO0102357A2 WO 2001002357 A2 WO2001002357 A2 WO 2001002357A2 GB 0002539 W GB0002539 W GB 0002539W WO 0102357 A2 WO0102357 A2 WO 0102357A2
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WO
WIPO (PCT)
Prior art keywords
hydrogen
compound
methyl
process according
ethyl
Prior art date
Application number
PCT/GB2000/002539
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English (en)
Other versions
WO2001002357A3 (fr
Inventor
Neal Ward
Original Assignee
Smithkline Beecham P.L.C.
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 P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to AU56946/00A priority Critical patent/AU5694600A/en
Publication of WO2001002357A2 publication Critical patent/WO2001002357A2/fr
Publication of WO2001002357A3 publication Critical patent/WO2001002357A3/fr

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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
    • 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
    • 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
    • C07D211/34—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—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 two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide

Definitions

  • the present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor.
  • This invention aims to overcome disadvantages in the existing processes for preparation of such compounds and so to provide alternative processes for their manufacture.
  • paroxetine may be prepared from a compound of structure (1) below in which R is methyl, X and Y are each two hydrogen atoms and Z is also hydrogen, that is 4-(4'-fluorophenyl)-3-hydroxymethyl-l-methylpiperidine, by reaction with 3,4-methylenedioxyphenol followed by demethylation.
  • 4-(4'-fluorophenyl)-3-hydroxymethyl-l -methyl piperidine is prepared by reduction of 4-(4'-fluorophenyl)-3-hydroxymethyl-l -methyl -1,2,3,6-tetrahydropyridine which is in turn prepared from 4-(4'-fluorophenyl)-l -methyl- 1,2,3,6-tetrahydropyridine by reaction with formaldehyde.
  • US 4007196 also describes the preparation of 4-(4'-fluorophenyl)-3- hydroxymethyl-1-methylpiperidine, by reduction of a compound of structure (1) in which R is methyl, X is oxygen, Y represents two hydrogen atoms and Z is a methyl group, that is 4-(4'-fluorophenyl)-3-methoxycarbonyl-l-methylpiperidine.
  • Alternative processes for the preparation of 4-(4'-fluorophenyl)-3-hydroxymethyl-l- methylpiperidine are given in EP-A-0223334 by reduction of a compound of structure (1) where R is a methyl group, X and Y are oxygen atoms and Z is a methyl or ethyl group.
  • paroxetine incorporates a fluorine atom in the 4-position of a phenyl ring, and it is well known that fluorine containing starting materials are more expensive than those containing other common substituents such as chlorine.
  • the 4-fluoro substituent is introduced at a very early stage, so that a significant proportion of the fluorine introduced at the beginning of the synthesis is lost during subsequent processing as by-products or unwanted isomers.
  • This invention provides a more efficient process for the preparation of 4-(4 '-fluorophenyl) piperidines of structure (1).
  • R is hydrogen or an alkyl, aralkyl, aryl, acyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl group or other conventional nitrogen protecting group
  • X and Y independently represent an oxygen atom or two hydrogen atoms
  • Z is hydrogen or a substituted or unsubstituted alkyl, aralkyl or aryl group, which comprises reacting a compound of structure (2)
  • A is a group capable of being replaced by fluorine, and R, X, Y and Z are as defined above, with a fluorinating agent.
  • the aryl moiety for example phenyl
  • the aryl moiety may be optionally substituted by one or more groups such as halogen or alkyl or alkoxy, or by two substituents linked to form a fused ring.
  • an especially suitable substituent Z is 3,4- methylenedioxyphenyl, as found in paroxetine.
  • Alkyl groups, including alkyl groups that are part of other moieties such as alkoxy or acyl, are typically C ⁇ -6 , especially CM groups, such as methyl and ethyl.
  • Suitable groups A include amino, protected amino (such as acetylamino or benzoylamino) hydrogen, nitro, chlorine, bromine, iodine or trimethylsilyl.
  • Especially preferred compounds of structure (2) are those where R is a hydrogen atom or a methyl or ethyl group.
  • the fluorination reaction is conveniently carried out via a diazonium salt intermediate using a reagent such as sodium nitrite and HF in pyridine at ambient or below ambient temperature using procedures analogous to those described in the Journal of Fluorine Chemistry (1991) volume 51 page 299, and Tetrahedron (1996) volume 52 page 23.
  • a reagent such as sodium nitrite and HF in pyridine
  • A represents groups such as hydrogen, nitro, chlorine, bromine, iodine or trimethylsilyl
  • the introduction of fluorine may be carried out by direct reaction with a fluorinating agent such as potassium fluoride, rubidium fluoride, tetramethylammonium fluoride or tetrabutylammonium fluoride at ambient or elevated temperature in a suitable solvent such as dimethyl sulphoxide, sulpholane, dimethyl formamide or tetrahydrofuran, using procedures analogous to those described in the Journal of Chemical Research, Synopses (1994) volume 12 page 478.
  • a fluorinating agent such as potassium fluoride, rubidium fluoride, tetramethylammonium fluoride or tetrabutylammonium fluoride at ambient or elevated temperature in a suitable solvent such as dimethyl sulphoxide, sulpholane, dimethyl formamide or tetrahydrofuran
  • the resulting compounds of structure (1) are either valuable chemical intermediates useful for the manufacture of important medicinal products, for example paroxetine hydrochloride, or are themselves active compounds, such as disclosed in US-A-3912743 and US-A-4007196.
  • Compounds of structure (2a) and (2b) and similar compounds may be prepared by the reaction of an ester of a suitably substituted cinnamic acid with a substituted malonic acid derivative using procedures analogous to those set out in EP-A-0223334.
  • an ester of a suitably substituted cinnamic acid with a substituted malonic acid derivative using procedures analogous to those set out in EP-A-0223334.
  • Compounds of structure (2c) and similar compounds may be prepared by the reaction of arecoline or analogues with other nitogen substituents with a suitably substituted Grignard reagent, following procedures analogous to those described in the Journal of Organic Chemistry (1957) volume 22 page 261.
  • a suitably substituted Grignard reagent for example the reaction of phenyl magnesium bromide with arecoline gives a compound of structure (2c) where A is hydrogen.
  • Compounds of structure (2c) may also be prepared by reduction of the corresponding pyridinium esters using methods analogous to those described in EP 0219934.
  • Compounds of structure (2d) may be prepared by reduction of compounds of structure (2a), (2b) or (2c) using a metal hydride such as lithium aluminium hydride as described in EP-A- 0223334 or US-A-4007196.
  • a metal hydride such as lithium aluminium hydride as described in EP-A- 0223334 or US-A-4007196.
  • Compounds of structure (2e) may be prepared by the reaction of compounds of structure (2d) with sesamol, as described in US-A-4007196.
  • Compounds of structure (2f) and similar compounds with other substituents on the ring nitrogen may be prepared by the reaction of compounds of structure (2e) with a chloroformic ester, for example phenyl chloroformate, chloroethyl chloroformate or vinyl chloroformate as described in US-A-4007196 and EP 0223403.
  • a chloroformic ester for example phenyl chloroformate, chloroethyl chloroformate or vinyl chloroformate as described in US-A-4007196 and EP 0223403.
  • Paroxetine is preferably obtained as the hydrochloride salt and most preferably as 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 especially paroxetine hydrochloride, obtained using this invention
  • 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 100 mg, for example 10 to 50 mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferably unit doses contain 20 mg 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 400 mg 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, including formulations adapted for controlled or delayed release.
  • 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 utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
  • 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 in solid or liquid form for the treatment or prophylaxis of the disorders
  • a solid sodium nitrite (70 mg, 1.0 mmol) was added in several portions for 5 minutes to a solution of l-methyl-3-hydroxymethyl-4-(4'-aminophenyl)pyridine in 15% hydrochloric acid (0.8 ml), cooled to 0°C, followed by a cool solution of ammonium tetrafluoroborate (0.3 g, 2.8 mmol) in water (0.9 ml) with vigorous stirring. The reaction mixture stirred overnight at 0°C and water was removed by lyophilization. The residue was covered by toluene (2 ml) and heated in a bath at 110°C.
  • a solution of the sulfonate in N,N-dimethylformamide (2 ml) was added to a freshly prepared solution of sodium sesamate [from sesamol (0.1 g, 0.71 mmol) and sodium hydride (60% dispersion in mineral oil, 0.029 g, 0.73 mmol)] in N,N-dimethylformamide (2 ml).
  • the reaction mixture was heated for 1.5 hours at 65°C, cooled to 25°C and partitioned between water (10 ml) and diethyl ether (20 ml). The aqueous phase was extracted with an additional amount of diethyl ether (20 ml) and discarded.
  • reaction products were extracted with dichloromethane (2 + 2 ml), the extracts were washed with water (2 and 2 ml), and brine (2 ml), dried with anhydrous sodium sulfate and evaporated to give 27 mg of the desired l-methyl-3-[(3,4-methylenedioxy-phenoxy)methyl]-4-(4'- aminophenyl)piperidine with 95% purity. Yield 68%.
  • reaction mixture was cooled to 20°C and partitioned between a 15% sodium hydroxide solution (0.5 ml) and ethyl acetate (2 ml). The organic phase was separated, washed with water (0.5 ml), dried with brine and anhydrous sodium sulfate, filtered and evaporated to afford the desired product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (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)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Pour préparer un composé de formule (1) on fait réagir un composé de formule (2) avec un agent fluorant.
PCT/GB2000/002539 1999-06-30 2000-06-30 Nouveau procede de preparation WO2001002357A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56946/00A AU5694600A (en) 1999-06-30 2000-06-30 Novel process

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9915303.3A GB9915303D0 (en) 1999-06-30 1999-06-30 Novel process
GB9915303.3 1999-06-30

Publications (2)

Publication Number Publication Date
WO2001002357A2 true WO2001002357A2 (fr) 2001-01-11
WO2001002357A3 WO2001002357A3 (fr) 2001-04-26

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/002539 WO2001002357A2 (fr) 1999-06-30 2000-06-30 Nouveau procede de preparation

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AU (1) AU5694600A (fr)
GB (1) GB9915303D0 (fr)
WO (1) WO2001002357A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2308986A1 (fr) 2006-05-17 2011-04-13 Pioneer Hi-Bred International Inc. Mini-chromosomes de plantes artificielles

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
US4902801A (en) * 1985-08-10 1990-02-20 Beecham Group Plc. Process for preparing aryl-piperidine carbinols and novel intermediates used in the process

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4007196A (en) * 1973-01-30 1977-02-08 A/S Ferrosan 4-Phenylpiperidine compounds
US4902801A (en) * 1985-08-10 1990-02-20 Beecham Group Plc. Process for preparing aryl-piperidine carbinols and novel intermediates used in the process

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AMAT M ET AL: "SYNTHESIS OF ENANTIOPURE 3,4-DISUBSTITUTED PIPERIDINES AN ASYMMETRIC SYNTHESIS OF (+)-PAROXETINE" TETRAHEDRON: ASYMMETRY,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 7, no. 6, 1 June 1996 (1996-06-01), pages 1591-1594, XP000647514 ISSN: 0957-4166 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2308986A1 (fr) 2006-05-17 2011-04-13 Pioneer Hi-Bred International Inc. Mini-chromosomes de plantes artificielles

Also Published As

Publication number Publication date
AU5694600A (en) 2001-01-22
WO2001002357A3 (fr) 2001-04-26
GB9915303D0 (en) 1999-09-01

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