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WO2009034434A2 - Procédé amélioré pour la préparation de o-desméthylvenlafaxine - Google Patents

Procédé amélioré pour la préparation de o-desméthylvenlafaxine Download PDF

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Publication number
WO2009034434A2
WO2009034434A2 PCT/IB2008/002323 IB2008002323W WO2009034434A2 WO 2009034434 A2 WO2009034434 A2 WO 2009034434A2 IB 2008002323 W IB2008002323 W IB 2008002323W WO 2009034434 A2 WO2009034434 A2 WO 2009034434A2
Authority
WO
WIPO (PCT)
Prior art keywords
desmethylvenlafaxine
preparation
venlafaxine
salt
sulfide
Prior art date
Application number
PCT/IB2008/002323
Other languages
English (en)
Other versions
WO2009034434A3 (fr
Inventor
Indravadan Ambalal Modi
Sanjay Muktawat
Udai Pratap Singh
Ramasubbu Chandrasekaran
Ravi Ponnaiah
Bakulesh Mafatlal Khamar
Original Assignee
Cadila Pharmaceuticals Limited
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 Cadila Pharmaceuticals Limited filed Critical Cadila Pharmaceuticals Limited
Publication of WO2009034434A2 publication Critical patent/WO2009034434A2/fr
Publication of WO2009034434A3 publication Critical patent/WO2009034434A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups

Definitions

  • the present invention relates to a process for the preparation of O-desmethyl-venlafaxine by O- demethylation of venlafaxine.
  • Venlafaxine ⁇ ( ⁇ ) 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol ⁇ is an antidepressant drug.
  • Venlafexine hydrochloride salt is available under the trade name Effexor®.
  • O-desmethylvenlafaxine is a major metabolite of venlafaxine. In vivo study suggests that O-desmethylvenlafaxine is a potent inhibitor of norepinephrine and dopamine uptake than venlafaxine.
  • US Patent No. 4535186 describes the preparation of O-desmethyl-venlafaxine by O- debenzylation of 1-[1-(4-benzyloxyphenyl)-2-(dimethylamino)ethyl]cyclohexanol. This method uses benzyl blocking groups, which leads to relatively low yield of the compound.
  • WO 2000/59851 publication describes a process for preparation of O- desmethylvenlafaxine, wherein venlafaxine is allowed to react with diphenylphosphide in THF at reflux temperature overnight. This process involves extraction steps using large volumes of solvents. The demethylation of venlafaxine becomes more problematic by the formation of a largely insoluble lithium salt of venlafaxine in the THF solvent.
  • WO 02/64543 publication discloses the use of alkali metal salt of a trialkyl borohydride (e.g. L-selectride) at a temperature from 60 0 C to 140 0 C to form alkali metal salt of the O- desmethyl-venlafaxine, which is converted to the free base of O-desmethyl-venlafaxine by neutralization with an acid.
  • This process of preparing O-desmethylvenlafaxine is relatively expensive due to higher cost of the reagents used.
  • US Patent No's. 6689912, 6673838 and 7026508 describe a process of preparing O- desmethylvenlafaxine, wherein venlafaxine is O-demethylated using high molecular weight thiolate anions such as 'dodeca'nethiol, benzenethiol in high boiling solvents like PEG-400. This process produces corresponding high molecular ' weight sulfur compounds as byproducts which are difficult to remove ' from the final 1 product.
  • US patent publication 20070299283 describes a process of preparing O- desmethylvenlafaxine from venlafaxine by using a demethylating agent metal sulfide, such as sodium sulfide and optionally selenium.
  • a demethylating agent metal sulfide such as sodium sulfide and optionally selenium.
  • the present invention provides a process for the preparation of O-desmethylvenlafaxine from venlafaxine or its salt, in high yield [ > 85 %] and purity [>99 %] wherein each impurity is ⁇ 0.1 %.
  • the main object of the present invention is to provide an improved process for the preparation of O-desmethylvenlafaxine by O-demethylation of venlafaxine or its salts.
  • Another object of the invention is to provide a process for preparing O- desmethylvenlafaxine from venlafaxine or its salt in high yield [> 85 %] and purity [>99 %] wherein each impurity is ⁇ 0.1 %.
  • Yet another object of the invention is to provide an alternative method for preparing O- desmethylvenlafaxine from venlafaxine or its salts.
  • Yet another object of the invention of the invention is to provide a process of making O- desmethylvenlafaxine from venlafaxine which produces low molecular weight sulfur compounds, which can be removed easily.
  • Yet another object of the invention is to provide a process with relatively shorter reaction times.
  • a process of preparing O- desmethylvenlafaxine comprises steps of demethylating a compound of Formula I to provide a compound of Formula Il using trimethyl silyl halide and metal sulfide in an organic solvent preferably ethereal solvent at elevated temperature as described in scheme I.
  • O-desmethylvenlafaxine refers to racemic mixtures or stereoisomerically pure forms of O-desmethylvenlafaxine, unless otherwise indicated.
  • O-demethlayation is carried out using metal sulfide and trimethylsilyl halide in high boiling ethereal solvents.
  • Halide can be chloride, bromide or iodide.
  • Metal sulfide compound used herein is one or more divalent sulfur atoms and at least one alkali metal such as sodium, potassium or alkaline earth metal. Examples of metal sulfide compounds include but are not limited to sodium sulfide (Na 2 S), potassium sulfide.
  • Sodium sulfide is preferably use in the demethylation process due to its relative low cost and ease in acquiring.
  • the solvent used for this reaction is selected from ethylene glycol, ethers of ethylene glycol such as PEG- 400, ethylene glycol monoethyl ether, Methylene glycol, polyethylene glycol preferably PEG- 400.
  • PEG-400 and sodium sulfide are mixed and stirred for about 65-70 0 C, TMS chloride is added to the mixture in 25-30 minutes, followed by addition of venlafaxine (or its salt).
  • the reaction mass is heated to about 150 0 C to 190 0 C, preferably at 165 0 C to 175 0 C.
  • the progress of the reaction is monitored by thin layer chromatography.
  • the reaction complete in about 4-8 hrs, preferably in 5-6 hrs.
  • the reaction mixture is cooled to about 65° C -70° C temperature, water is added.
  • the pH of the reaction mass is adjusted to -9.5 using a mineral acid, preferably an aqueous hydrochloric acid; precipitates obtained thereof is stirred, filtered and washed with water.
  • the residue is taken in water, pH is adjusted to ⁇ 5.0 - 5.2 using a mineral acid, preferably an aqueous hydrochloric acid.
  • the reaction, mass is filtered and the pH of aqueous phase is adjusted to 9.5 -10 using a base.
  • the base is selected from carbonates, bicarbonates of alkali metals, triethyl amine, ammonia, diethyl amine, preferably ammonia.
  • the precipitate are filtered, washed with water and dried.
  • O-desmethyl venlafaxine produced has > 85 % yield and purity > 99.0 %, wherein each impurity is ⁇ 0.1%.
  • the present invention is illustrated by following non-limiting examples.
  • Trimethylsilyl chloride (17.0 gm), PEG 400 (25.0 ml) and Na 2 S (49.1 gm) were stirred for 30 minutes.
  • To this reaction mass/ venlafaxine (5.0 gm) in PEG-400 (20 ml) was added.
  • the reaction mixture was heated to 160-170 0 C for 7 hrs and cooled to 65-70 0 C.
  • Water was added to the reaction mass and the pH was adjusted to 3.5 using H 3 PO 4 .
  • the organic byproducts were removed by extraction using heptane (25.0 ml).
  • the pH of aqueous layer was adjusted to 9.5 -
  • Trimethylsilyl chloride (6.1 gm), PEG-400 (25.0 ml) and Na 2 S (11.3 gm) were stirred for 30 minutes.
  • venlafaxine (5.0 gm) in PEG 400 (20 ml) was added.
  • the reaction mixture was heated to 160-170 0 C for 8 hrs.
  • the reaction mass was cooled to 65-70 0 C.
  • Water was added to the reaction mass and the pH was adjusted to about 3.5 using phosphoric acid.
  • the organic byproducts were removed by extraction with heptane (25.0 ml) and toluene (20.0 ml).
  • the pH of aqueous layer was adjusted to 9.5-10 using aqueous NH 3 .
  • the precipitates were filtered.
  • PEG-400 750 ml and sodium sulfide (750 gms) were stirred and heated to 65-70 0 C.
  • Trimethylsilyl chloride 200 ml was added at 65 0 C in 25 to 30 minutes.
  • Venlafaxine 150 gms was added and the reaction mixture was heated to 165°-170°C. The temperature of the reaction mixture was maintained of about 160 - 170 0 C for about 6-8 hrs. The progress of the reaction was monitored by TLC.
  • the reaction mass was cooled to 65-70 0 C. Water was added to the reaction mass and pH was adjusted to 9.5 using aqueous HCI. The reaction mixture was stirred for one hour and filtered, washed with water [1.0 Liter].
  • the wet cake was taken up in water and pH was adjusted to 5.0 - 5.2 using aqueous HCI.
  • the reaction mass was stirred for 30 minutes and filtered.
  • the filtrate was alkalized using aqueous ammonia till pH -9.5 was achieved.
  • the reaction mass was filtered, an4 washed with water and dried.
  • Product Yield is -88 % (126 gms) and Purity is -99.47 %.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne un nouveau procédé pour la préparation de O-desméthylvenlafaxine à partir de venlafaxine ou de son sel. On effectue une O-déméthylation de la venlafaxine ou de son sel pour produire de la O-desméthylvenlafaxine avec un rendement de production élevé et une pureté élevée en faisant réagir la venlafaxine ou son sel avec un halogénure de triméthylsilyle et un sulfure de métal à haute température, en utilisant un ou plusieurs solvants éthérés de point d'ébullition élevé. On isole la O-desméthylvenlafaxine par désactivation avec de l'eau suivie de l'ajustement du pH et on l'isole à pH ~9,5 à 10. Le procédé évite la formation de composés du soufre de masse moléculaire élevée. La O-desméthylvenlafaxine est produite avec un rendement de production élevé (> 85 %) et une pureté élevée (> 99,0), chaque impureté étant < 0,1 %.
PCT/IB2008/002323 2007-09-10 2008-09-09 Procédé amélioré pour la préparation de o-desméthylvenlafaxine WO2009034434A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1720/MUM/2007 2007-09-10
IN1720MU2007 2007-09-10

Publications (2)

Publication Number Publication Date
WO2009034434A2 true WO2009034434A2 (fr) 2009-03-19
WO2009034434A3 WO2009034434A3 (fr) 2009-12-30

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Family Applications (1)

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WO (1) WO2009034434A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011124190A2 (fr) 2010-04-06 2011-10-13 Zentiva, K.S. Procédé de préparation de phénols-4-(1-(1-hydroxycyclohexyl)-2-(substitué)éthyl) par o-déméthylation de leurs éthers méthyliques au moyen de thiols aromatiques inodores
EP2394976A1 (fr) 2010-06-11 2011-12-14 LEK Pharmaceuticals d.d. Procédé pour déméthyler des éthers méthyliques aromatiques à l'aide d'acide mercaptopropionique

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA80543C2 (en) * 2001-12-04 2007-10-10 Wyeth Corp Method for the preparation of o-desmethylvenlafaxine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011124190A2 (fr) 2010-04-06 2011-10-13 Zentiva, K.S. Procédé de préparation de phénols-4-(1-(1-hydroxycyclohexyl)-2-(substitué)éthyl) par o-déméthylation de leurs éthers méthyliques au moyen de thiols aromatiques inodores
EP2394976A1 (fr) 2010-06-11 2011-12-14 LEK Pharmaceuticals d.d. Procédé pour déméthyler des éthers méthyliques aromatiques à l'aide d'acide mercaptopropionique
WO2011154152A1 (fr) 2010-06-11 2011-12-15 Lek Pharmaceuticals D.D. Procédé de déméthylation des éthers de méthyle aromatiques à l'aide d'acide 3-mercaptopropionique

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Publication number Publication date
WO2009034434A3 (fr) 2009-12-30

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