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WO2002018337A1 - Processus de racemisation d'un intermediaire utile dans la preparation de paroxetine - Google Patents

Processus de racemisation d'un intermediaire utile dans la preparation de paroxetine Download PDF

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Publication number
WO2002018337A1
WO2002018337A1 PCT/EP2001/009997 EP0109997W WO0218337A1 WO 2002018337 A1 WO2002018337 A1 WO 2002018337A1 EP 0109997 W EP0109997 W EP 0109997W WO 0218337 A1 WO0218337 A1 WO 0218337A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
paroxetine
mixture
give
Prior art date
Application number
PCT/EP2001/009997
Other languages
English (en)
Inventor
Dean Riley
Original Assignee
Basf Aktiengesellschaft
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 Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to AU2001289851A priority Critical patent/AU2001289851A1/en
Publication of WO2002018337A1 publication Critical patent/WO2002018337A1/fr

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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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member 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
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • This inventio - relates to a process for the racemisation of 5 enatiomerically enriched l-benzyl-3-hydroxymethyl-4- (4-fluoro- phenyl)piperidine which is a useful 5 intermediate in the preparation of paroxetine.
  • WO 98/01424 discloses a process for the preparation of racemic trans-l-benzyl-3- hydroxymethyl-4- (4-fluorophenyl)piperidine in which 4-(4-fluoro- phenyl) -N-benzyl-1, 2 , 5, ⁇ -tetrahydropyridine is reacted with 5 formaldehyde in acidic medium via the Prins reaction to give the desired product.
  • One of the optional next stages for the process is the resolution of this compound with an optically active acid, preferably dibenzoyltartaric acid to give the individual enantiomers of trans-l-benzyl-3-hydroxymethyl- 0 4- (4-fluorophenyl)piperidine.
  • the present invention provides a process for the racemisation of a compound of formula I comprising the steps of
  • the amine protecting group is one which is inert to reduction by a metal hydride.
  • the amine protecting group is selected from a) allyl, b) benzhydryl, c) methoxymethyl, d) benzylo ' xymethyl, e) tetrahydropyranyl , f) an optionally substituted benzyl group, g) di (p-methoxyphenyl)methyl, h) tri- phenylmethyl, i) (p-methoxyphenyl) diphenylmethyl , j) diphenyl- 4-pyridylmethyl , k) 2 , 4, 6-trimethylbenzenesulphonyl, 1) toluene- sulphonyl, m) benzylsulphonyl, n) a C ⁇ _ 6 alkyl group, o) a tri- fluoro C ⁇ _ 4 alkyl group, p) an alkynyl
  • the amine protecting group is a benzyl group which is optionally substituted on the phenyl ring by one or more of the following groups: a C ⁇ _ 4 alkyl group, a C 1 -. 4 alkoxy group, halo or nitro. Most preferably R ⁇ represents benzyl .
  • the oxidising agent is selected from the group consisting of chromium trioxide preferably in the form known as Jones ' reagent .
  • the amount of oxidising agent used is in the range of ' 1 to 3 molar equivalents with respect to the amount of compound of formula I used. Preferably 1.5 to 2.5 molar equivalents is used and most preferably around 2 molar equivalents is used.
  • the base is selected from the group consisting of an alkali metal hydroxide, alkali metal alkoxide, lithium diiso- propylamide, lithium hexamethyldisilylazide, or potassium hexamethyldisilylazide .
  • the amount of base used is in the range oft to 12 molar equivalents with respect to the amount of compound of formula II used.
  • the amount of base used is in the range of 2 to 4 molar equivalents with respect to the amount of compound of formula II used.
  • the reducing agent is selected from diisobutylaluminium hydride, aluminium hydride, sodium bis- (2-methoxyethoxy) aluminium hydride, a lithium di(C ⁇ -. 4 alkoxy) aluminium hydride or sodium diethylaluminium hydride or mixtures thereof.
  • the metal hydride is diisobutylaluminium hydride.
  • the amount of reducing agent used is in the range of 1.5 to 3 molar equivalents with respect to the amount of substan- tially racemic compound of formula II used.
  • the diluent is an organic liquid which is inert to the metal hydride employed and is preferably a solvent for the compound of formula II.
  • the diluent is an ether or a hydrocarbon or a mixture thereof . More preferably the diluent is selected from tetrahydrofuran, toluene, dioxane, diethyl ether, diisopropyl ether, t-butylmethyl ether, diglyme, ethylene glycol dimethyl ether or mixtures thereo . Most preferably the diluent is tetra hydrofuran.
  • the amount of the diluent is in the range of 1 part by weight to 100 parts by weight with respect to the compound of formula II employed.
  • the amount of the diluent is in the range of 2 parts by weight to 50 parts by weight with respect to the compound of formula II employed. More preferably the amount of the diluent is in the range of 3 parts by weight to 10 parts by weight with respect to the compound of formula II employed.
  • the process is carried out at a temperature in the range of -70°C to the boiling point of the diluent employed.
  • the process is carried out at a temperature in the range 0-150°C. More preferably the process is carried out at a temperature in the range 0-100°C. Most preferably the process is carried out at a temperature in the range 50-70°C.
  • the present invention provides novel compounds of formula II in which R is as defined above which are useful as intermediates in the preparation of paroxetine.
  • R is benzyl .
  • the present invention provides a process for the preparation of paroxetine from a compound of formula I according to the methods described in WO 96/36636, and WO 98/01424 characterised in that the compound of formula I was prepared by racemisation of an enantiomerically enriched compound of formula I by the process of the present invention.
  • the paroxetine may be obtained as the hydrochloride salt as the anhydrous form or the hemihydrate or other solvate.
  • the process of the present invention may also be used in conjunction with the process described in WO 98/52920 to prepare an intermediate which may be further processed as described below to produce paroxetine . These combination processes also form part of the present invention.
  • the process of the present invention is advantageous because it provides a pure precursor to paroxetine.
  • Paroxetine may be obtained in a pure form from compounds of formula I by a) conversion of the hydroxy group into a leaving group, for example halo or tosyloxy, b) reaction with sesamol or a salt thereof, c) removal of the protecting group Ri by conventional means for example by hydrogenolysis when Ri is benzyl and optionally d) salt formation, for example the hydrochloride salt as the anhydrous form or the hemihydrate .
  • enantiomerically enriched should be understood to Tttean that the compound of formula I has an enantiomeric excess of one enantiomer over the other enanatiomer in the range of 1 to 100%, preferably an enantiomeric excess in the range of 50 to 100%, and more preferably an enantiomeric excess in the range of 70 to 100%.
  • either enantiomer may predominate in the enantiomerically enriched compound.
  • the predominant enantiomer is the (+) enantiomer. More preferably the predominant enantiomer is the (-) enantiomer.
  • substantially racemic means that there is an enantiomeric excess of less than 20% preferably less than 10% and most preferably less than 5%.
  • the invention is illustrated by the following Examples which are given by way of example only.
  • the final product of each of these Examples was characterised by one or more of the following procedures : gas-liquid chromatography; high performance liquid chromatography,- elemental analysis; nuclear magnetic resonance spectroscopy and infrared spectroscopy.
  • Jones reagent was prepared by dissolving chromium trioxide (0.67 g) in water (1 ml), cooling the solution in an ice water bath and then adding concentrated sulphuric acid (0.6 ml) drop- wise with stirring. A precipitate was formed. Water (1 ml) was added dropwise to dissolve the solid and leave a clear red solution of Jones reagent. The Jones reagent was added dropwise to a stirred solution of (+) -lbenzyl-3-hydroxymethyl-4- (4-fluoro- phenyl) -1, 2, 3 , 6-tetrahydropyridine (1.0 g) in acetone (50 ml). The mixture was stirred for 10 minutes.
  • Propan-2-ol (1 ml) was added to the reaction mixture followed by water (15 ml) and then trisodium citrate (4.5 g) followed by three lumps of mossy zinc. The mixture was stirred for 50 minutes and then ether (50 ml) was added. The mixture was stirred for 10 minutes and then the organic layer was separated. The aqueous layer was extracted with ether (2 x 50 ml) . The combined organic extracts were dried, filtered and evaporated to give an emulsion containing acetone and water.
  • the aqueous layer was washed with ether (20 ml) and the combined ether washes and extracts were dried, filtered and evaporated to give a non-acidic material (0.1 g) which was discarded.
  • the basic aqueous layer was acidified to pH 6 - 7 by the dropwise addition of concentrated hydro- chloric acid. A colourless precipitate was formed, this was extracted into a mixture of ether (15 ml) and ethyl acetate (15 ml) but much of the solid failed to dissolve.
  • the biphasic mixture was filtered to give a colourless solid (which was discarded after NMR analysis showed no organic material) and a clear biphasic filtrate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un processus de racémisation d'une 1-benzyl-3-hydroxyméthyl-4-(4-fluorophényl)pipéridine énantiomériquement enrichie qui est un intermédiaire utile dans la préparation de paroxétine.
PCT/EP2001/009997 2000-08-30 2001-08-30 Processus de racemisation d'un intermediaire utile dans la preparation de paroxetine WO2002018337A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001289851A AU2001289851A1 (en) 2000-08-30 2001-08-30 Process for the racemisation of an intermediate useful in the preparation of paroxetine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0021145.8 2000-08-30
GB0021145A GB0021145D0 (en) 2000-08-30 2000-08-30 Chemical process

Publications (1)

Publication Number Publication Date
WO2002018337A1 true WO2002018337A1 (fr) 2002-03-07

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PCT/EP2001/009997 WO2002018337A1 (fr) 2000-08-30 2001-08-30 Processus de racemisation d'un intermediaire utile dans la preparation de paroxetine

Country Status (3)

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AU (1) AU2001289851A1 (fr)
GB (1) GB0021145D0 (fr)
WO (1) WO2002018337A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117964546A (zh) * 2024-03-28 2024-05-03 成都硕德药业有限公司 一种尼拉帕利中间体的制备方法

Citations (4)

* 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
EP0300617A1 (fr) * 1987-06-23 1989-01-25 Beecham Group Plc Procédé pour la préparation de carbinols d'arylpipéridine
WO1996036636A1 (fr) * 1995-05-17 1996-11-21 Novo Nordisk A/S Procede de preparation de derives de 4-arylpiperidine
WO1998001424A1 (fr) * 1996-07-08 1998-01-15 Richter Gedeon Vegyészeti Gyár Rt. Derives de n-benzylpiperidine et de tetrahydropyridine

Patent Citations (4)

* 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
EP0300617A1 (fr) * 1987-06-23 1989-01-25 Beecham Group Plc Procédé pour la préparation de carbinols d'arylpipéridine
WO1996036636A1 (fr) * 1995-05-17 1996-11-21 Novo Nordisk A/S Procede de preparation de derives de 4-arylpiperidine
WO1998001424A1 (fr) * 1996-07-08 1998-01-15 Richter Gedeon Vegyészeti Gyár Rt. Derives de n-benzylpiperidine et de tetrahydropyridine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117964546A (zh) * 2024-03-28 2024-05-03 成都硕德药业有限公司 一种尼拉帕利中间体的制备方法
CN117964546B (zh) * 2024-03-28 2024-06-11 成都硕德药业有限公司 一种尼拉帕利中间体的制备方法

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Publication number Publication date
GB0021145D0 (en) 2000-10-11
AU2001289851A1 (en) 2002-03-13

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