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WO2009084038A2 - Procédé amélioré d'élaboration d'o-desméthyl venlafaxine - Google Patents

Procédé amélioré d'élaboration d'o-desméthyl venlafaxine Download PDF

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Publication number
WO2009084038A2
WO2009084038A2 PCT/IN2008/000856 IN2008000856W WO2009084038A2 WO 2009084038 A2 WO2009084038 A2 WO 2009084038A2 IN 2008000856 W IN2008000856 W IN 2008000856W WO 2009084038 A2 WO2009084038 A2 WO 2009084038A2
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WO
WIPO (PCT)
Prior art keywords
process according
venlafaxine
acid
desmethyl
solvent
Prior art date
Application number
PCT/IN2008/000856
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English (en)
Other versions
WO2009084038A3 (fr
Inventor
Chidambaram Venkateswaran Srinivasan
Ashvin Kumar Aggarwal
Gurdeep Singh Sarin
Lalit Wadhwa
Original Assignee
Ind-Swift Laboratories Limited
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Filing date
Publication date
Application filed by Ind-Swift Laboratories Limited filed Critical Ind-Swift Laboratories Limited
Publication of WO2009084038A2 publication Critical patent/WO2009084038A2/fr
Publication of WO2009084038A3 publication Critical patent/WO2009084038A3/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to an improved process for the preparation of O-desmethyl- venlafaxine, a venlafaxine metabolite, and pharmaceutically acceptable salts thereof.
  • 0-Desmethyl-venlafaxine of formula I is a major metabolite of venlafaxine and has been shown to inhibit norepinephrine and serotonin uptake and is chemically named as l-[2-(dimethylamino)-l - (4-phenol) ethyl]-cyclohexanol.
  • ⁇ 9-Desmethyl-venlafaxine was first disclosed in U.S. Patent No. 4,535,186 wherein it is exemplified as a fumarate salt.
  • the process for the preparation of 0-desmethyl-venIafaxine includes the reaction of p-benzyloxyphenylacetic acid with dimethyl amine in the presence of oxalyl chloride to obtain 4-benzyloxy-7V,iV-dimethylbenzene acetamide which is further reacted with cyclohexanone in the presence of butyl lithium at a temperature of -70 0 C to yield l -[(4- benzyloxyphenyl)[(dimethylamino) carbonyljmethyl]cyclohexanol which is then hydrogenated using lithium aluminium hydride to l-[l-(4-benzyloxyphenyI)-2-
  • U.S. patent no. 6,673,838 discloses a process of preparing 0-desmethyl-venlafaxine by demethylating venlafaxine with high molecular weight alkane, arene or arylalkyl thiolate anion such as straight or branched chain thiolate anions having 8-20 carbon atoms, mono or bicyclic arene thiolate anions having 6 to 10 carbon atoms, or mono or bicyclic arylalkyl thiolate anions having 7 to 12 carbon atom, which are very expensive and are not commercially available, hence unviable for industrial use.
  • This patent also discloses demethylation of venlafaxine with an alkali metal salt of a trialkylborohydrides such as selectride (tri-sec-butylborohydride) or triethylborohydride.
  • a trialkylborohydrides such as selectride (tri-sec-butylborohydride) or triethylborohydride.
  • selectride tri-sec-butylborohydride
  • triethylborohydride triethylborohydride
  • U.S. patent no. 6,342,533 discloses a process of preparing 0-desmethyl-venlafaxinc by demethylating venlafaxine with diphenylphosphide in tetrahydrofuran (generated by adding n-butyl lithium to diphenylphosphine in tetrahydrofuran below 0°C) at reflux for an overnight period.
  • Diphenylphosphine and n-butyl lithium are moisture sensitive, difficult to handle and are not industrial friendly.
  • the method involves extraction steps using large volumes of solvent.
  • PCT publication no. WO 2007/071404 discloses a process of preparing O-desmethyl-venlafaxine by demethylating venlafaxine with metal sulfide such as sodium sulfide or potassium polysulfide in dipolar aprotic solvent such as 1-methylpyrrolidone under heating and in presence of selenium.
  • metal sulfide such as sodium sulfide or potassium polysulfide in dipolar aprotic solvent such as 1-methylpyrrolidone under heating and in presence of selenium.
  • Metal sulfide can react with acids rapidly to produce hydrogen sulfide gas, which is a highly toxic and foul smelling gas.
  • PCT publication no. WO 2007/120923 discloses a process of preparing substantially pure O- desmethyl-venlafaxine by demethylating venlafaxine with thiophenol, sodium sulfide, and a Ci-C 8 alkyl thiolate in an organic solvent with heating.
  • This application also discloses two more methods for the preparation of ⁇ 9-desmethyl-venlafaxine, first method explains specific use of thiophenol for demethylation in non hydroxylic or non ethereal solvent in presence of a base catalyst such as alkali metal carbonate under heating and in second method didesmethylvenlafaxine is first demethylated with thiolate in high boiling point solvent followed by N-methylation of tridcsmethyl venlafaxine to get substantially pure O-desmethyl-venlafaxine.
  • This patent application discloses multi step preparation of O-desmethyl-venlafaxine which is time consuming and not suitable for large scale production.
  • the present invention provides an industrially advantageous process of making 0-desmethyl- venlafaxine in high yield and purity by demethylation of venlafaxine using mild reaction conditions and less hazardous reagents.
  • the process of present invention is convenient to operate on a commercial scale and gives the desired product in good yield and quality.
  • the principal and foremost object of the present invention is to provide an improved process for the preparation of O-desmethyl-venlafaxine in good yield and quality which is efficient, industrially advantageous and convenient to operate on industrial scale.
  • Another object of the present invention is to provide a process for the preparation of Odesmelhyl- venlafaxine by employing mild reaction conditions.
  • the present invention provides an improved process for the preparation of O- desmethyl-venlafaxine of Formula I,
  • Figure 1 shows a powdered X-ray diffraction pattern (PXRD) of (9-desmethyl venlafaxine.
  • Figure 2 shows a differential scanning calorimetric thermogram (DSC) of 0-desmethyl- venlafaxine.
  • Figure 3 shows an infra-red spectrum (IR) of 0-desmethyl-venlafaxine.
  • the present invention provides an improved process for the preparation of (9-desmcthyl- venlafaxine of Formula I or pharmaceutically acceptable salts thereof by demethylation of venlafaxine of Formula II or its sajt using mild demethylating reagents like alkali and alkaline earth metal salts of mercapto acids and their derivatives such as ester, amide etc., mcrcapto alcohols, heterocyclic mercaptans, xanthates, thioacids and the like.
  • thioacetic acid is employed.
  • the starting material, venlafaxine or its salts may be procured from the market or may be prepared in accordance with procedures known in the art such as described in U.S. Pat. Nos. 4,535, 186, and 5,043,466 and PCT publication no. WO 2007/049302.
  • the salts of the starting material, venlafaxine can be formed conventionally by reaction of the free base with an equivalent amount of corresponding acid.
  • the acids are either inorganic or organic, including hydrochloric, hydrobromic, fumaric, maleic, succinic, sulfuric, phosphoric, tartaric, acetic, citric, oxalic and similar acids.
  • demethylation of venlafaxine or its salt is performed using alkali or alkaline earth metal salts of mercapto acids and their derivatives such as ester, amide etc., mercapto alcohols, heterocyclic mercaptans, xanthates and thioacids which arc readily available and industrially viable.
  • alkali and alkaline earth metal salts of mercapto acids and their derivatives such as ester, amide etc., mcrcapto alcohols, heterocyclic mercaptans, xanthates. and thioacids hence the final product is obtained in good yield and purity.
  • alkali and alkaline earth metal salts of mercapto acids and their derivatives such as ester, amide etc., mercapto alcohols, heterocyclic mercaptans, xanthales and thioacids can be selected from mercapto acids such as thioglycolic acid, aromatic mercapto acids; mercaptoacetates such as methyl mercaptoacetates; mercaptoamides such as mercaptoacetamides; mercapto alcohols such as 2-mercaptoethanol; thioacids such as thioacetic acid, xanthates such as potassium or sodium xanthates; heterocyclic mercaptans such as 2- mercaptobenzoxazole, 2-mercaptobenzthiazo'le; and the like or mixture thereof. Most preferably salt of thioglycolic acid is employed in demethylation of venlafaxine.
  • alkali and alkaline earth metal salts of mercapto acids and their derivatives such as ester, amide etc., mercapto alcohols, heterocyclic mercaptans, xanthates and thioacids is taken as 2-10 mole equivalents, more preferably 3- 7 mole equivalents and most preferably 4- 6 mole equivalents.
  • the demethylation reaction involves the addition of alkali or alkaline metal salt of mercapto acids and their derivatives such as ester, amide etc., mercapto alcohols, heterocyclic mercaptans, xanthates and thioacids to the venlafaxine base or salt thereof in the presence of organic solvent.
  • the reaction is performed at a temperature of from about ambient temperature to about 220 0 C, more preferably from about 50 0 C to about 21O 0 C, and most preferably from about 150 0 C to about 200 0 C.
  • the reaction mass is stirred for few minutes to few hours, preferably the reaction mass is stirred for a period of about 10-80 hours at 130-200 0 C.
  • the solvent employed for the demethylation includes but not limited to halogenated solvents such as dichloroethane, aliphatic esters such as butyl acetate, aliphatic amides such as iV ⁇ iV'-dimethylacetamide, N', ⁇ P- dimethylformamide, iV-methyl-2-pyrrolidone; aliphatic ketones such as methyl isobutyllcetone; aromatic hydrocarbons such as toluene; diol such as ethylene glycol, methylene glycol, PEG600 and the like and mixtures thereof.
  • halogenated solvents such as dichloroethane, aliphatic esters such as butyl acetate, aliphatic amides such as iV ⁇ iV'-dimethylacetamide, N', ⁇ P- dimethylformamide, iV-methyl-2-pyrrolidone; aliphatic ketones such as methyl isobutyllcetone; aromatic hydrocarbons such as tol
  • the solvent employed is selected from N-methyl-2- pyrrolidone or N'.TV'-dimethylacetamide. It is advantageous when the quantity of solvent taken is about three to seventeen times with respect to the starting material more preferably quantity of solvent taken is about five to fifteen times.
  • reaction completion can be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) for the presence or absence of starting material.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • the reaction is generally conducted until, ideally, not more than 1% of the starting material remains.
  • the solvent is removed by suitable techniques like evaporation or distillation under vacuum.
  • Alkali or alkaline metal salts of above described demethylating agent employed in the process of present invention can be used as such for the reaction or can be generated insitu in the reaction mixture for demethylation of venlafaxine.
  • demethylating agent is dissolved in a suitable solvent in the presence of source of alkali or alkali metal ion and stirred at ambient temperature to form their alkali or alkali metal salts.
  • the solvent used for the generation of the alkali or alkaline metal salts of the demethylating agent are same as employed for the demethylation reaction (as described above).
  • Source of alkali or alkali metal ion include but not limited to alkali or alkali metal hydroxides, carbonates, bicarbonates or hydride, alkoxide thereof.
  • the source of alkali or alkali metal ion is sodium hydride.
  • the demethylation reaction can be performed in the presence or absence of phase transfer catalyst.
  • the phase transfer catalyst employed can be selected from amongst, but not limited to tetraalkylammonium or phosphonium halide such as tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulphate, crown ethers like 15- crown-5, 18-crown-6, and the like.
  • the catalyst employed is tetrabutylammonium bromide.
  • 0-Desmethyl-venlafaxine prepared by the process of present invention can be isolated from the reaction mass by any suitable technique known in the art.
  • the isolation of O-desmethyl- venlafaxine from reaction mass can further be performed in two ways.
  • the pH of the reaction mass is adjusted to 8-10 with organic or mineral acid such as hydrochloric acid, sulphuric acid or acetic acid.
  • the pH is preferably adjusted to 8.5-9.2 with concentrated hydrochloric acid.
  • the precipitated solid is further stirred for few minutes to few hours, preferably 1 hour at a temperature of below 20°C and isolated.
  • the pH of the reaction mass is adjusted to 1-2 with organic or mineral acid.
  • the pH is preferably adjusted to 1.2-1.4 with dilute hydrochloric acid.
  • the aqueous layer is washed with organic solvents and treated with adsorbent to assist in impurity removal; it is effective to treat the substrate with active charcoal.
  • Organic solvent include halogenated solvent such as dichloromethane; ester such as ethylacetate or hydrocarbon solvent such as cyclohexane and the like or mixture thereof.
  • the pH of the aqueous layer is adjusted to 8-10 with suitable base at a temperature of below 20 °C, preferably 10-15 0 C. Base used can be organic or inorganic base.
  • Inorganic base include alkali metal bicarbonates, carbonates or hydroxides thereof.
  • Organic base include amine base such as triethylamine and the like. Preferably saturated aqueous potassium carbonate solution is used. The precipitated solid is further stirred for a period of 1 hour at a temperature of below 20 °C, preferably 10-15 °C and then isolated.
  • the precipitated product obtained by either of the two processes can be isolated by the methods known in prior art preferably by filtration. However, other equivalent separation or isolation procedures could, also be used.
  • the wet solid is then washed with demineralized water to give pure Odesmethyl-venlafaxine.
  • the product is found to be free from the above impurity or having impurity up to an amount less than 1%, preferably less than 0.5%, most preferably less than 0.1%.
  • the (9-desmethyl-venlafaxine so formed can optionally be purified with a suitable solvent to give (9-desmethyl-venlafaxine in purity above 99% by HPLC.
  • the solvent employed can be selected from, but is not limited to alcohol, esters, halogenated solvents, nitriles, ketones, aromatic hydrocarbon or mixtures thereof; preferably the solvent employed is selected from isopropyl alcohol, ethyl acetate or mixtures thereof.
  • O-Desmethyl-venlafaxine so formed by the process of the present invention, is characterized by at least one of Karl Fisher or TGA, powdered X-Ray diffraction (PXRD), Infra-red spectroscopy (IR) or differential scanning calorimetry (DSC).
  • O-Desmethyl-venlafaxine as prepared by the process of present invention is having about less than 0.7% moisture by weight as measured by Karl Fisher or Thermogravimetric analysis (TGA).
  • the moisture content is less than 0.5% by weight, most preferably less than 0.1% by weight.
  • O-Desmethyl-venlafaxine so synthesized displays X-ray powder diffraction pattern as shown in Fig.l.
  • DSC differential scanning calorimetric thermogram
  • X-ray diffraction of O-desmethyl-venlafaxine is measured on a PANalytical X'Pcrt Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities.
  • PANalytical X'Pcrt Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities.
  • O-Desmethyl-venlafaxine so formed can be optionally converted to its pharmaceutically acceptable acid addition salt by suspending the free base of O-desmethyl-venlafaxine along with the corresponding acid in a suitable solvent for a time sufficient to convert to its pharmaceutically acceptable acid addition salt.
  • Pharmaceutically acceptable acid addition salt includes inorganic or organic salt, selected from, but are not limited to, hydrochloric, hydrobromic, fumaric, maleic, succinic, tartarate, sulfuric, phosphoric, tartaric, acetic, and citric acid.
  • O-desmethyl- venlafaxine is isolated as corresponding succinate salt.
  • the order of adding or mixing the reactant used in the process of present invention does not matter and does not change the composition of the product formed.
  • Example -1 Preparation of 0-desmethyI-venIafaxine
  • the aqueous layer was washed with dichloromcthanc (2x40 ml) and treated with activated carbon. After charcoalization the pH of the aqueous layer was adjusted to 8.7 with saturated aqueous potassium carbonate solution at 10-15 °C. The precipitated solid was stirred for 30 minutes at 15-20 0 C and filtered. The wet solid was washed with demincralizcd water (3x40 ml) and recrystallized with isopropyl alcohol (40 ml) to obtain 6.95 g (yield 73.47 %) of title compound as white powder having purity 98.87% by HPLC.
  • the aqueous layer was washed with dichloromethane (40 ml x 3) and treated with activated carbon. After charcoal ization, the pH of the aqueous layer was adjusted to 8.7 with aqueous potassium carbonate solution at 10-20 °C. The precipitated solid was stirred for lhour at 10-20 °C and filtered. The wet solid was washed with demineralized water (50 ml x 2) and recrystallized with isopropyl alcohol (50 ml) to obtain 7 g (yield 74%) of title compound as white powder having purity 99.95% by HPLC.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé industriellement intéressant pour l'élaboration d'O-desméthyl venlafaxine, d'un métabolite de venlafaxine, et de certains de ses sels pharmaceutiquement admis, par déméthylation de la venlafaxine ou de ses sels au moyen d'un alcalin ou de sels de métaux alcalinoterreux d'acides mercapto et de leurs dérivés, d'alcools mercapto, de mercaptans hétérocycliques, de xanthates et d'acides thio et analogues ou de leurs mélanges en présence d'un solvant organique.
PCT/IN2008/000856 2007-12-28 2008-12-23 Procédé amélioré d'élaboration d'o-desméthyl venlafaxine WO2009084038A2 (fr)

Applications Claiming Priority (2)

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IN2766DE2007 2007-12-28
IN2766/DEL/2007 2007-12-28

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WO2009084038A2 true WO2009084038A2 (fr) 2009-07-09
WO2009084038A3 WO2009084038A3 (fr) 2011-01-27

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011007136A2 (fr) 2009-07-16 2011-01-20 Cipla Limited Procédé pour la préparation d'o-déméthyl-venlafaxine et intermédiaire destiné à être utilisé dans celui-ci
US20110098506A1 (en) * 2009-10-26 2011-04-28 Intas Pharmaceuticals Limited Method of preparing o-desmethylvenlafaxine
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
CN103724173A (zh) * 2013-12-11 2014-04-16 安徽丰乐香料有限责任公司 一种覆盆子酮的合成方法
CN114478271A (zh) * 2021-12-13 2022-05-13 植恩生物技术股份有限公司 琥珀酸去甲文拉法辛制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003048104A1 (fr) * 2001-12-04 2003-06-12 Wyeth Procedes de preparation de o-desmethyle venlafaxine
WO2007120923A1 (fr) * 2006-04-17 2007-10-25 Teva Pharmaceutical Industries Ltd. O-desméthylvenlafaxine essentiellement pure et ses procédés de préparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003048104A1 (fr) * 2001-12-04 2003-06-12 Wyeth Procedes de preparation de o-desmethyle venlafaxine
WO2007120923A1 (fr) * 2006-04-17 2007-10-25 Teva Pharmaceutical Industries Ltd. O-desméthylvenlafaxine essentiellement pure et ses procédés de préparation

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011007136A2 (fr) 2009-07-16 2011-01-20 Cipla Limited Procédé pour la préparation d'o-déméthyl-venlafaxine et intermédiaire destiné à être utilisé dans celui-ci
US9012689B2 (en) 2009-07-16 2015-04-21 Cipla Limited Process for the preparation of O-desmethyl venlafaxine and intermediate for use therein
US20110098506A1 (en) * 2009-10-26 2011-04-28 Intas Pharmaceuticals Limited Method of preparing o-desmethylvenlafaxine
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
CN103724173A (zh) * 2013-12-11 2014-04-16 安徽丰乐香料有限责任公司 一种覆盆子酮的合成方法
CN114478271A (zh) * 2021-12-13 2022-05-13 植恩生物技术股份有限公司 琥珀酸去甲文拉法辛制备方法
CN114478271B (zh) * 2021-12-13 2024-05-31 植恩生物技术股份有限公司 琥珀酸去甲文拉法辛制备方法

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