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WO2006035457A1 - Procede de fabrication de venlafaxine et d'intermediaires associes - Google Patents

Procede de fabrication de venlafaxine et d'intermediaires associes Download PDF

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Publication number
WO2006035457A1
WO2006035457A1 PCT/IN2005/000314 IN2005000314W WO2006035457A1 WO 2006035457 A1 WO2006035457 A1 WO 2006035457A1 IN 2005000314 W IN2005000314 W IN 2005000314W WO 2006035457 A1 WO2006035457 A1 WO 2006035457A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
venlafaxine
iii
catalyst
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/IN2005/000314
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English (en)
Inventor
Uday Balkrishna Gokhale
Chandrashekar Parenky
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.)
Amoli Organics Ltd
Original Assignee
Amoli Organics Ltd
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 Amoli Organics Ltd filed Critical Amoli Organics Ltd
Publication of WO2006035457A1 publication Critical patent/WO2006035457A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • 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
    • C07C213/02—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 involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the 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 a process for manufacturing Venlafaxine hydrochloride and intermediates thereof.
  • Venlafaxine is known by the chemical name 1-[2-dimethylamino-1-(4 methoxyphenyl ethyl Cyclohexanol hydrochloride and structure of formula (V).
  • Venlafaxine is a useful pharmaceutical agent as an antidepressant.
  • Venlafaxine, the intermediates in the manufacture of Venlafaxine, the process of preparing said Venlafaxine and their intermediates are well known from US Patents 4,535,186, US Patent No. 6,350,912, and CN 1225356.
  • WO03/050074 discloses the manufacture of Venlafaxine Hydrochloride and crystalline polymorphs Form I, Form II, Form III and optically pure (R) and (S) enantiomers exhibiting different crystalline structures of Venlafaxine hydrochloride. The preparation of all the forms of Venlafaxine and their inter-conversion are also described in said WO03/0500074 publication.
  • Patents 4535186, 4761501 disclose a process for manufacture of 1-[2- amino-i-(p-methoxyphenyl) ethyljcyclohexanol (free base of formula IV), an intermediate produced during the preparation of Venlafaxine in two stages by reacting p-methoxyphenyl acetonitrile with cyclohexanone in the presence of n- butyl lithium (Stage 1) to form 1-[cyano(p-methoxyphenyl) methyl] Cyclohexanol of formula III
  • WO/03/050074 suggests an alternate way of preparing compound of formula III without using butyl lithium i.e. by reacting p-methoxyphenyl acetonitrile with cyclohexanone in the presence of alkali metal hydroxide in a mixture of toluene and hexane.
  • the publication WO/03/050074 also suggests a material yield of 74% based upon p-methoxyphenyl acetonitrile and purity.
  • the second stage i.e. conversion of compound of formula III to formula IV described in US patent US 4,535,186 is by hydrogenating compound of formula III using Rhodium on alumina.
  • the catalyst Rhodium is recycled by filtering and washing the catalyst with ethanol and the combined filtrate evaporated and dried under vacuum yielding free base as an oil.
  • the cost of Rhodium catalyst is very high and hence the catalyst has to be recovered.
  • WO/02/500017 suggests the use of a Nickel or cobalt catalyst for the hydrogenation, which is highly economical when compared with the Rhodium catalyst as suggested by US Patent No. 4,535,186.
  • the International Publication WO/02/500017 teaches that the hydrogenation reaction of Stage Il may be carried out in the presence of an organic solvent preferably an alcohol.
  • the international publication also suggests the pretreatment of the catalyst with ethanol.
  • the US Patent 4,535,186 describes the third stage in the process of preparing Venlafaxine i.e. conversion of compound of formula IV (free base) to compound V i.e. Venlafaxine by methylating the compound of formula IV (free base) with a mixture of formaldehyde and formic acid in water.
  • US Patent Publication No. 2005/0033088 describes a process for preparing phenylethylamine derivative, an intermediate of Venlafaxine hydrochloride; said process comprising steps of reduction of compound of formula III with palladium on charcoal in an organic acid selected from formic acid, acetic acid or propionic acid, preferably acetic acid in an autoclave at a pressure of 5 to 25 kg/cm2 preferably 10 to 15 kg/cm2 at a temperature in the range of 30 to 75°C, preferably at 50 to 55°C till the hydrogenation substantially complete, filtering the palladium catalyst and evaporating the filtrate. Extracting the filtrate with halogenated hydrocarbon solvent and purifying the same.
  • the process also describes the preparation of Venlafaxine hydrochloride without isolation of freebase.
  • the object of the present invention is to provide an improved process for preparing compound of formula IV, that increases the purity and yield of said compound of formula - V.
  • Another object of the present invention is to provide a safer industrial operation for easy handling of butyl lithium during coupling reaction for preparing compound of formula III, i.e. 1-[cyano-(4-methoxyphenyl) methyl ] cyclohexanol
  • Another object of the present invention is to provide an improved process for manufacturing compound of formula III with high yield and purity.
  • Further object of the present invention is to provide an economically viable method of preparing Venlafaxine thereby reducing the cost of production.
  • Yet another object of the present invention is to reduce the number of steps in the preparation of venlafaxine.
  • the first aspect of the invention provides a process for preparing compound of formula IV an intermediate for preparing Venlafaxine using Raney Nickel as a catalyst in the presence of toluene and water.
  • the process comprises the step of hydrogenating a compound of formula-Ill:
  • the catalyst used in the present invention is Raney Nickel.
  • Raney nickel prepared from Nickel Aluminum alloy with Ni content of 90-92% and aluminum content of 8 - 10%. Particle size of the catalyst may vary from about 150 to about 250 mesh.
  • the catalyst Raney Nickel is washed with water to make it alkali free.
  • the use of the solvent toluene/ water produces a good yield of about 66% of the compound of formula IV with 99% HPLC purity.
  • the process of the present invention uses water as a bulk solvent and toluene as a co-solvent. . Toluene is used as a co-solvent in the amounts of about 20% by volume.
  • the second aspect of the invention provides a process for preparing a compound of formula III.
  • the third aspect of the invention provides a process for preparing Venlafaxine a compound of formula V.
  • the said process comprising steps of preparing compound of formula (III) according to Step 1 of present invention; preparing compound of formula ((IV) according to step Il of present invention; methylating the compound of formula (IV) by formaldehyde and formic acid mixture wherein the purity of compound (V) is 99.9% by HPLC with a yield of 84%.
  • the fourth aspect of the invention provides a process for preparing compound of formula IV by hydrogenating compound of formula III in the presence of Nickel catalyst and water
  • the improved process for preparing Venlafaxine and the intermediates thereof according to the present invention provides an economically viable process with 89% yield of the intermediate 1-[cyano-(4-methoxyphenyl) methyl] Cyclohexanol, with 66% molar yield of 1-[2-amino-1-(4-methoxyphenyl)ethyl cyclohexanol] acetate and with an overall molar yield of 50% of Venlafaxine of 99.9% HPLC purity.
  • Use of water as a bulk solvent reduces the cost of manufacture of the Venlafaxine and its intermediates considerably with substantially good yield and purity as that of the prior art processes.
  • Venlafaxine produced by this procedure exhibits following characteristic x-ray powder diffraction pattern with characteristic peaks expressed in d-values (A) at.
  • the present invention relates to an improved process for the preparation of compound of formula IV
  • the compound of formula IV is further methylated using formaldehyde and formic acid mixture to form Venlafaxine (formula V) followed by the treatment with HCL gas dissolved in Isopropanol.
  • Venlafaxine produced by this procedure exhibits following characteristic x-ray powder diffraction pattern with characteristic peaks expressed in d-values (A) at.
  • the present invention uses a novel solvent toluene / water for the preparation of compound of formula IV.
  • the use of the solvent toluene /water produces a good yield of 66% of compound of formula IV with 99% HPLC purity.
  • the process of the present invention uses water as a bulk solvent and toluene as a co-solvent. .
  • Toluene is used as a co-solvent in the amounts of about 20% by volume.
  • reaction product is retained in toluene and acetate salt is isolated from this toluene extract.
  • water as a bulk solvent reduces the cost of manufacture of the Venlafaxine and its intermediates considerably with substantially good yield and purity as that of the prior art processes.
  • nickel catalyst preferably Raney nickel catalyst is used.
  • the catalyst is washed in water to remove the alkali. No pretreatment of the nickel catalyst is required.
  • compound of formula IV is prepared by hydrogenating compound of formula III in the presence of Raney Nickel and water.
  • compound of formula III is prepared by charging p-methoxyphenyl acetonitrile into butyl lithium at -70 to -75°C and tetrahydrofuran; cooling the reaction mixture to about -50°C to -75 0 C; adding cyclohexanone at a temperature below -50 0 C quenching with ice and saturated ammonium chloride solution below 0 ° C; and stirring and filtering the product of formula (III) wherein the said process yields 89% of compound of formula III with 99.8% purity.
  • the reaction scheme is depicted as follows:
  • reaction mixture was gradually added over mixture of ice and 150 ml saturated ammonium chloride solution below 0°C and adjusted pH to 7 with dilute Hydrochloric acid. Stirred for 1 hr and filtered the product. Washed the product with 200 ml hexane and dried to obtain 74.3 gm. (The yield based on p-methoxyphenyl acetonitrile 89%, Melting range 123- 125°C, HPLC purity of 99.8%).

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

Abstract

La présente invention concerne un procédé amélioré de préparation de Venlafaxine et d'intermédiaires associés. Cette invention a aussi pour objet un procédé de préparation d'un composé de formule (IV), un intermédiaire destiné à la préparation de Venlafaxine par hydrogénation d'un composé de formule (III) en présence de toluène, d'eau et de nickel de Raney en tant que catalyseur, ledit procédé produisant 66 % du composé de formule (IV) avec une pureté CLHP de 99 %. Le composé de formule (III) est préparé par addition de gouttelettes d'acétonitrile de p-méthoxyphènyle, en tant que solution du tétrahydrofurane, à la solution de lithium de butyle dans l'hexane, ledit procédé produisant 89 % du composé de formule (III) avec une pureté de 99,8 %.
PCT/IN2005/000314 2004-09-17 2005-09-16 Procede de fabrication de venlafaxine et d'intermediaires associes Ceased WO2006035457A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN997/MUM/2004 2004-09-17
IN997MU2004 2004-09-17

Publications (1)

Publication Number Publication Date
WO2006035457A1 true WO2006035457A1 (fr) 2006-04-06

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ID=35810870

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000314 Ceased WO2006035457A1 (fr) 2004-09-17 2005-09-16 Procede de fabrication de venlafaxine et d'intermediaires associes

Country Status (1)

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WO (1) WO2006035457A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008059525A3 (fr) * 2006-09-29 2008-07-10 Calyx Chemicals And Pharmaceut Procédé amélioré pour la préparation de venlafaxine et ses analogues
CN113429303A (zh) * 2021-07-26 2021-09-24 合肥华方医药科技有限公司 一种工业化生产盐酸文拉法辛的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4535186A (en) * 1983-04-19 1985-08-13 American Home Products Corporation 2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives
WO2003050074A1 (fr) * 2001-12-13 2003-06-19 Cadila Healthcare Limited Fabrication de l'hydrochlorure venlafaxine et de polymorphes cristallins de celui-ci

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4535186A (en) * 1983-04-19 1985-08-13 American Home Products Corporation 2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives
WO2003050074A1 (fr) * 2001-12-13 2003-06-19 Cadila Healthcare Limited Fabrication de l'hydrochlorure venlafaxine et de polymorphes cristallins de celui-ci

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008059525A3 (fr) * 2006-09-29 2008-07-10 Calyx Chemicals And Pharmaceut Procédé amélioré pour la préparation de venlafaxine et ses analogues
CN113429303A (zh) * 2021-07-26 2021-09-24 合肥华方医药科技有限公司 一种工业化生产盐酸文拉法辛的方法
CN113429303B (zh) * 2021-07-26 2023-07-14 合肥华方医药科技有限公司 一种工业化生产盐酸文拉法辛的方法

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