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WO2006008635A1 - Procede de preparation d'un derive 3-phenoxy-pyridine - Google Patents

Procede de preparation d'un derive 3-phenoxy-pyridine Download PDF

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Publication number
WO2006008635A1
WO2006008635A1 PCT/IB2005/002037 IB2005002037W WO2006008635A1 WO 2006008635 A1 WO2006008635 A1 WO 2006008635A1 IB 2005002037 W IB2005002037 W IB 2005002037W WO 2006008635 A1 WO2006008635 A1 WO 2006008635A1
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WO
WIPO (PCT)
Prior art keywords
compound
reaction
formula
solvent
vii
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.)
Ceased
Application number
PCT/IB2005/002037
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English (en)
Inventor
Robert Walton
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.)
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Original Assignee
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
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
Priority claimed from GB0415753A external-priority patent/GB0415753D0/en
Application filed by Pfizer Corp Belgium, Pfizer Ltd Great Britain, Pfizer Corp SRL filed Critical Pfizer Corp Belgium
Publication of WO2006008635A1 publication Critical patent/WO2006008635A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms

Definitions

  • the present invention is concerned with an improved process for the preparation of the selective serotonin reuptake inhibitor ⁇ /-Methyl ⁇ 3-[3-methyl-4- (methylthio)phenoxy]-4-pyridyl ⁇ methylamine (L) or (D) tartrate and with intermediate products therein.
  • WO 02/083643 describes the preparation of ⁇ /-Methyl ⁇ 3-[3-methyl-4- (methylthio)phenoxy]-4-pyridyl ⁇ methylamine (L) tartrate (I) 1 in which the compound is prepared by (a) reaction of 3-chloroisonicotinonitrile (II) with 3- methyl-4-(methylthio)phenol (III) in the presence of potassium carbonate in a suitable solvent such as ⁇ /, ⁇ /-dimethylformamide (DMF), at elevated temperature; (b) carrying out a hydrolysis of 3-[3-methyl-4-
  • Reaction times for process step (a) are slow when carried out on a large scale, typically 18 to 24 hours. Additionally, the work-up procedure for process step (a) requires large volumes of solvent. This is impractical on an industrial scale, as it is time consuming (a significant economic disadvantage), and most notably because a large amount of waste solvent must be disposed of after the product has been isolated. Also, the product obtained must be purified by column chromatography; again this is not desirable when preparing large amounts of product.
  • reaction quench in process step (d) involves addition of methanol followed by 6M HCI( aq ). Such a two-step process involving large volumes of solvent is undesirable on a large scale.
  • step (e) the formation of salt (I) is carried out using a large volume of isopropyl alcohol.
  • the isolation of salt (I) is then achieved via two recrystallisations from ethanol. Such an inefficient process is economically costly on an industrial scale.
  • compounds of formula (IV) are prepared by reaction of 3-chloroisonicotinonitrile (II) with 3-methyl-4-(methylthio)phenol (III) in a suitable solvent, at elevated temperature; followed by a work-up; characterised by performing the reaction in the presence of a base having particle size D g0 ⁇ 900 microns and VMD ⁇ 500 microns.
  • the base is potassium carbonate of particle size Dgo ⁇ 9OO microns and VMD ⁇ 500 microns.
  • the work-up consists of the slow addition of water to the stirred reaction mixture at 60 0 C, followed by collection of the crystallised product, compound (IV).
  • Suitable bases include carbonate bases such as sodium carbonate, caesium carbonate; butoxide bases such as potassium t-butoxide, lithium t- butoxide, sodium t-butoxide; hydroxide bases such as sodium hydroxide; and organic bases such as pyridine and morpholine.
  • Suitable reaction solvents include polar aprotic solvents such as ⁇ /-methyl-2- pyrrolidinone (NMP), tetrahydrofuran, dimethylsulfoxide, dioxan, acetonitrile and ethers.
  • polar aprotic solvents such as ⁇ /-methyl-2- pyrrolidinone (NMP), tetrahydrofuran, dimethylsulfoxide, dioxan, acetonitrile and ethers.
  • Compounds of formula (V) are prepared by process step (b), hydrolysis of a compound of formula (IV).
  • the reaction is carried out using a suitable base in a suitable solvent, at elevated temperature, followed by quenching with a suitable acid; characterised by the purification of the crude product by slurrying in water, at 40-70 0 C, followed by filtration and drying.
  • Suitable bases include KOH (aq) , and LiOH (aq) .
  • Suitable solvents include methanol, isopropyl alcohol, n-butanol, t-butanol, 2- butanol, t-amyl alcohol and tetrahydrofuran.
  • Suitable acids include concentrated H 2 SO 4 ( aq) , HBr (a q ) , and aqueous acetic acid.
  • the preferred base is 1 M-2.5M NaOH (aq ).
  • the amide (Vl) is generated by process step (c), reaction of acid (V) with carbonyldiimidazole (CDI) in a suitable solvent, followed by addition of a suitable methylamine source; characterised by the distillation and replacement of the reaction solvent with fe/f-butyl methyl ether (TBME), and the isolation of the product by crystallisation.
  • Suitable solvents include DCM, f-BuOMe, and ethyl acetate.
  • Suitable sources of methylamine include methylamine gas, and salts of methylamine in the presence of a base (a suitable salt would include hydrochloride, suitable bases would include triethylamine and DMAP).
  • the preferred solvent is DCM.
  • the product containing TBME solution may be washed with NaOH (aq ), NH 4 CI (aq) and water, prior to the isolation of the product by crystallisation.
  • Compound (VII) is prepared by process step (d), reduction of amide (Vl) using a suitable reducing agent in a suitable solvent; characterised by the direct quenching of the reaction by the addition of a solution of a suitable acid in a suitable solvent.
  • the THF is preferably distilled and replaced with water. This solution is adjusted to pH12 by the addition of 40% NaOH (aq) , and then extracted with f-BuOMe.
  • Suitable solutions of acids include HCI( aq ), H 2 SO 4 ( aq ), HBr( aq ), and aqueous acetic acid, in a suitable solvent such as THF.
  • the preferred acid solution is 6M HCI (aq) /THF
  • Suitable reaction solvents include dioxan, and methyl THF ethers.
  • Suitable reducing agents include LiAIH 4 , solutions of AIH 3 , DIBAL-H, catalytic hydrogenation, NaBH 4 /BF 3 .THF, and BF 3 -Et 2 O.
  • Compound (I) is prepared by process step (e), addition of D or L tartaric acid to compound (VII), in a suitable solvent optionally at elevated temperature.
  • Suitable solvents include aqueous ethanol, methanol, methyl ethyl ketone, acetone, n-butanol, t-butanol, 2-butanol, t-amyl alcohol, and THF (all as aqueous mixtures).
  • the preferred solvent is aqueous ethanol.
  • the L form of tartaric acid is used.
  • compound (I) is obtained by recrystallisation from a suitable solvent, such as aqueous ethanol, methanol, methyl ethyl ketone, acetone, n-butanol, t-butanol, 2-butanol, t-amyl alcohol, and THF (all as aqueous mixtures).
  • a suitable solvent such as aqueous ethanol, methanol, methyl ethyl ketone, acetone, n-butanol, t-butanol, 2-butanol, t-amyl alcohol, and THF (all as aqueous mixtures).
  • compound (I) is recrystallised from aqueous ethanol.
  • process steps (d) and (e) are combined to avoid the isolation of compound (VII).
  • preferred conditions for process step (d) are THF as solvent and NaBH 4 /BF 3 .THF as reducing agent.
  • compound (VII) is isolated as a solution in TBME, by extraction with TBME. This solvent is then preferably distilled and replaced with ethanol.
  • preferred conditions for process step (e) are aqueous ethanol as solvent, and use of the L form of tartaric acid.
  • process step (b) the development of a slurrying process for the work up, has the advantage of reducing the volume of solvent required. This process also facilitates the removal of the NH 4 CI by-product, thus preventing the formation of the carboxamide by-product in process step (c).
  • reaction quench in process step (d) involves addition of a 6M HCI (aq) /THF mixture. This allows the resultant hydrogen evolution to be controlled, thus making it a safer procedure. This improved method is highly advantageous on a large scale as only one quench need be carried out, and as a result, far less solvent is used.
  • the invention also encompasses a further embodiment that provides an alternative synthesis of compound (VII). This embodiment is illustrated by the following reaction scheme:
  • Aldehyde (IX) can be prepared by process step (a), reaction of 3- chloronicotinaldehyde (VIII; prepared by reaction of 3-chloropyridine with Lithium diisopropylamide in DMF at -78 0 C) with phenol (III), in the presence of potassium carbonate in a suitable solvent such as DMF.
  • Compound (VII) is then prepared from aldehyde (IX) by process step (f), reductive amination.
  • Methylamine is the amine source and NaBH 4 is the reducing agent. The reaction is carried out in a suitable solvent such as THF.
  • aldehyde (IX) can be prepared by process step (g), reduction of nitrile (IV) with DIBAL (diisobutylaluminium hydride) in a suitable solvent such as THF; as illustrated by scheme 3 below.
  • DIBAL diisobutylaluminium hydride
  • NMR spectra were obtained using a Varian Inova 300 MHz spectrometer by dissolving the sample in an appropriate solvent.
  • Mass spectra were obtained using a LC/MS system consisting of an 1100 series Hewlett Packard LC in combination with a Micromass ZMD mass spectrometer.
  • the product can be further purified by the following method:
  • the reaction mixture was cooled to -1O 0 C and the 6N HCI solution was added slowly keeping the temperature ⁇ 10°C.
  • the suspension was heated at 50 0 C for 90 mins then cooled to 22°C.
  • the solvent was reduced to minimum volume to remove THF and replaced with de-ionised water to leave a final water volume of 300ml.
  • the reaction was cooled to 22 0 C, charged with TBME (120ml) and the mixture stirred for 10 mins.
  • the aqueous phase was recharged to the vessel along with TBME (200ml).

Landscapes

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

Abstract

La présente invention concerne un procédé amélioré de préparation de l'inhibiteur sélectif de la capture de la sérotonine, le N-Méthyl{3-[3-méthyl-4-(méthylthio)phénoxy]-4-pyridyl}méthylamine (L) ou (D) tartrate (I) et les produits intermédiaires présentés. Formule (I)
PCT/IB2005/002037 2004-07-14 2005-07-01 Procede de preparation d'un derive 3-phenoxy-pyridine Ceased WO2006008635A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0415753A GB0415753D0 (en) 2004-07-14 2004-07-14 Improved process for the preparation of a biphenyl ether compound
GB0415753.3 2004-07-14
US59808804P 2004-08-02 2004-08-02
US60/598,088 2004-08-02

Publications (1)

Publication Number Publication Date
WO2006008635A1 true WO2006008635A1 (fr) 2006-01-26

Family

ID=34972169

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/002037 Ceased WO2006008635A1 (fr) 2004-07-14 2005-07-01 Procede de preparation d'un derive 3-phenoxy-pyridine

Country Status (1)

Country Link
WO (1) WO2006008635A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083643A1 (fr) * 2001-04-11 2002-10-24 Pfizer Limited Derives de phenyle heterocyclyle ether utilises comme inhibiteurs du recaptage de la serotonine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083643A1 (fr) * 2001-04-11 2002-10-24 Pfizer Limited Derives de phenyle heterocyclyle ether utilises comme inhibiteurs du recaptage de la serotonine

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