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WO2010079046A1 - Procédé de préparation de la desvenlafaxine et sels d'addition d'acide de celle-ci pharmaceutiquement acceptables - Google Patents

Procédé de préparation de la desvenlafaxine et sels d'addition d'acide de celle-ci pharmaceutiquement acceptables Download PDF

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Publication number
WO2010079046A1
WO2010079046A1 PCT/EP2009/067041 EP2009067041W WO2010079046A1 WO 2010079046 A1 WO2010079046 A1 WO 2010079046A1 EP 2009067041 W EP2009067041 W EP 2009067041W WO 2010079046 A1 WO2010079046 A1 WO 2010079046A1
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WO
WIPO (PCT)
Prior art keywords
desvenlafaxine
venlafaxine
process according
alkyl
alkyl aluminium
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/EP2009/067041
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English (en)
Inventor
Andrés Molina Ponce
Jesús Angel GRACIA GARCIA
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Chemo Iberica SA
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Chemo Iberica SA
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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
    • 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
    • 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
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having 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 the preparation of desvenlafaxine and pharmaceutically acceptable acid addition salts thereof.
  • Desvenlafaxine is also known as O-demethyl-venlafaxine and it is the major metabolite of venlafaxine (( ⁇ )-(1 -[2-(dimethylamine)-1 -(4-methoxyphenyl)ethyl] cyclohexanol).
  • Desvenlafaxine acts as a norepinephrine and serotonin uptake inhibitor and it is indicated for the treatment of depression. Its chemical name is ( ⁇ )-1 -[2-(dimethylamine)-1 -(4-hydroxyphenyl)ethyl]cyclohexanol and the corresponding chemical formula is:
  • Desvenlafaxine was first disclosed in EP-B-112669 as a free base and as a fumarate salt. Other salts of desvenlafaxine have been disclosed in the art, for example its succinate salt is disclosed in EP-B-1360169. Desvenlafaxine differs from venlafaxine in that the phenol moiety is demethylated. Thus, the more relevant processes for the preparation of desvenlafaxine known in the art comprise the demethylation of venlafaxine.
  • Demethylation applied to phenol deprotection is based in the rupture of an arylmethylether group.
  • This type of reaction is generally carried out by acids, including Lewis acids (AICI 3 , BBr 3 ), and bases.
  • acids including Lewis acids (AICI 3 , BBr 3 ), and bases.
  • AICI 3 , BBr 3 Lewis acids
  • bases bases
  • the demethylation process for the preparation of desvenlafaxine requires the rupture of an arylmethylether group in the presence of a tertiary alcohol group, which is very sensitive to said acidic conditions giving rise to a dehydration reaction to yield the corresponding alkene in such extent that in some cases can became the main reaction.
  • Patent applications WO-A-200059851 , WO-A-200032555 and WO-A-200032556 disclose a process for the preparation of desvenlafaxine consisting in the demethylation of venlafaxine by reaction with lithium diphenylphosphide in tetrahydrofurane as solvent. This reaction requires the use of a great amount of solvent.
  • the reaction is carried out in tetrahydrofurane with a very low concentration of venlafaxine, probably due to the low solubility of the venlafaxine lithium salt formed during the reaction and, second, during the isolation of the product a great amount of solvent has to be used because the product is extracted at pH 6.8-6.9 in ethyl acetate wherein desvenlafaxine is quite insoluble.
  • Patent application WO-A-200264543 shows a process for the demethylation of venlafaxine by a thalkylborohydride metallic salt (particularly L-selectride).
  • the reaction requires long reaction times, 19 hours, rendering a yield of 90.7% and a purity of 98.8%.
  • trial kylborohydrides for demethylation renders a number of dangerous boron derivatives as side-products.
  • L-selectride results in the formation of tris(1 -methylpropanyl)borane and ths(1 -methylpropyl)boroxine which must be deactivated by oxidation or hydrolysis.
  • L-selectride is an expensive reagent.
  • Patent application WO-A-2003048104 relates to a process comprising the demethylation of venlafaxine with dodecanethiol or benzenethiol in the presence of a methanol solution of sodium methanolate and polyethylenglycol 400 as solvent. Those conditions render low yields, such as 77.5% when using dodecanethiol and 19% when using benzenethiol. Beside this, as has been seen by the authors of patent application WO 2007/120923, the products obtained by that processes show low richness (74% or 78%) and purity (73% or 95%). The process is generally impaired by the requirement of using high temperatures and the difficulty of recycling the solvent used.
  • the demethylation process disclosed in the application WO-A-2007071404 comprises the reaction of venlafaxine with a metallic sulphide, such as sodium sulphide hydrate, optionally in the presence of selenium and
  • Patent application WO-A-2007120923 provides a demethylation process comprising combining at reduced pressure venlafaxine, a reagent selected from thiophenol, sodium ethanethiolate or sodium sulphide and a solvent with a high boiling point, such as dimethylformamide, N-methylpyrrolidone or dimethylacetamide.
  • a reagent selected from thiophenol, sodium ethanethiolate or sodium sulphide and a solvent with a high boiling point, such as dimethylformamide, N-methylpyrrolidone or dimethylacetamide.
  • High reaction temperatures between 135-19O 0 C are used.
  • thiophenol or sodium ethanethiolate yields are not provided, but very low richness between 52-93% and purities between 95-99.8% are disclosed.
  • sodium sulphide is used as reagent, the product is obtained with notably increased richness and purity reaching values greater than 90%.
  • the reagents used are thiol
  • WO-A-2008090465 describes the use of 2-(diethylamino)ethanethiol or the hydrochloride thereof, in the presence of sodium methanolate and polyethyleneglycol, for the demethylation of venlafaxine. Again, it is required to heat the mixture at high temperatures (195 0 C), and low yields (45%) and a moderate purity (96.8%) are obtained.
  • the authors of the present invention have found a new process for the industrial preparation of desvenlafaxine that allows to obtain the product with good yield and high purity. Further, it has to be noted the use of costless and commercially available reagents and the high reproducibility of the process, while avoiding the use of toxic and stinking reagents such as thiolates.
  • an object of the invention is a process for the preparation of desvenlafaxine comprising the demethylation of venlafaxine or a salt of venlafaxine with an alkyl aluminium or alkyl aluminium hydride compound wherein the alkyl group is a lineal or branched (Ci-C 4 )alkyl group, and, optionally forming a pharmaceutically acceptable salt.
  • Another object of the invention is the use of an alkylaluminium or an alkylaluminium hydride compound wherein the alkyl group is a lineal or branched (Ci-C 4 )alkyl group to carry out a process of demethylation of venlafaxine.
  • the process for the preparation of desvenlafaxine by the demethylation of venlafaxine or a salt thereof is carried out by using an alkyl aluminium or alkyl aluminium hydride compound of formula AIR 1 R 2 R 3 , wherein R-I, R 2 , and R 3 are the same or different and are selected from hydrogen or linear or branched (d-C 4 )alkyl groups.
  • the process for the preparation of desvenlafaxine comprises:
  • Venlafaxine used as starting material in the process of the present invention can be prepared according to any process known in the art, for example, the process described in EP-B-112669.
  • a venlafaxine salt is used, preferably it is a salt which is not able to be reduced, for example the hydrochloride salt.
  • the alkyl aluminium or alkyl aluminium hydride compound used in the process of the present invention is a compound of formula Al R 1 R 2 R 3 wherein R 1 and R 2 are the same and are a (C- ⁇ -C 4 )alkyl group and R 3 is H or R 1 , preferably wherein R 1 and R 2 are ethyl, n-butyl or isobutyl, more preferably wherein R 1 and R 2 are isobutyl.
  • the compounds are diisobutylaluminium hydride (DIBAL) or triisobutylaluminium (TIBA).
  • aluminium compound comprises a free hydroxyl group.
  • a fraction of the reagent employed reacts with the hydroxyl group yielding aluminium complexes that are hydrolyzed in the course of the reaction for regenerating the hydroxyl group.
  • the reaction between venlafaxine and the alkyl aluminium or alkyl aluminium hydride compound is carried out in a solvent which is inert toward the reagents and wherein venlafaxine is, at least, partially soluble.
  • organic solvents are aromatic hydrocarbons, such as toluene or xylene; aliphatic hydrocarbons, such as hexane; cyclic hydrocarbons, such as cyclopentane and cyclohexane and mixtures thereof.
  • the solvent used is toluene.
  • the process of the present invention is carried out advantageously by the controlled addition of a solution of venlafaxine in the inert solvent over the solution of the aluminium compound in the inert solvent, provided that venlafaxine is totally soluble in said solvent. Otherwise, it will be preferred to add the solution of the aluminium compound over the suspension of venlafaxine in the selected solvent.
  • the solution is cooled at room temperature, between 20° C and 30° C, and the excess of the aluminium compound is hydrolyzed pouring the reaction mixture over water.
  • the reactions involving aluminium reagents require the removal from the reaction medium of the aluminium salts formed after hydrolyzing the excess of reagent in order to subsequently isolate the reaction product.
  • the reaction mixture is treated with a diluted aqueous solution of an acid, thus the aluminium salts are solubilized in water and the product is isolated by filtration or extraction with an organic solvent.
  • the reaction mixture can be hydrolyzed only with water, and, if desired, with a diluted aqueous solution of sodium hydroxide, and then the precipitated aluminium salts are removed by filtration.
  • the process of the present invention further comprises hydrolyzing with water the excess of alkyl aluminium or alkyl aluminium hydride compound, adjusting the pH of the mixture to 5.0, and removing the formed aluminium salts by filtration.
  • desvenlafaxine is not soluble in water in its neutral form (isoelectric point)
  • desvenlafaxine hydrochloride can be converted in its free base form by the methods known in the art, such as the neutralization with a base (for example, until its isoelectric point).
  • a pharmaceutically acceptable acid addition salt can be obtained, if desired, starting from the aqueous solution containing the desvenlafaxine hydrochloride, without the need of isolating the free base, by treating it with an alkaline or alkaline earth salt of the selected acid. This process is suitable when the desired addition salt is not soluble in water.
  • the pharmaceutically acceptable acid addition salt can be obtained from the isolated desvenlafaxine base, as described above, by the addition of the corresponding acid over the base of desvenlafaxine in a selected solvent.
  • pharmaceutically acceptable acid addition salt refers to salts which are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, or sulphuric acid, or organic acids, such as fumaric acid, succinic acid, aspartic acid, formic acid, citric acid, tartaric acid or maleic acid.
  • the salt is preferably formed with fumaric acid.
  • the pharmaceutically acceptable salt is desvenlafaxine fumarate.
  • Desvenlafaxine fumarate can be prepared by the addition of an aqueous solution of disodium fumarate over an aqueous solution of desvenlafaxine hydrochloride, obtained after the demethylation of venlafaxine and the removal of the aluminium salts, and subsequently adjusting the pH to about 3.7 in order to convert the fumarate sodium salt of desvenlafaxine into the corresponding acid form. It also can be prepared by the addition of fumaric acid over a suspension of desvenlafaxine in ethanol/acetone or ethanol. The crystalline product obtained is isolated by filtration.
  • the conversion of desvenlafaxine base to the fumarate salt is carried out without the isolation of the base.
  • the term "desvenlafaxine fumarate”, refers to any acid addition salt obtained by the reaction of desvenlafaxine with fumaric acid.
  • the obtained salt is desvenlafaxine fumarate (1 :1 ).
  • the molecule of desvenlafaxine has a chiral centre.
  • the present invention includes the racemic mixtures of the compound and the pure stereoisomers.
  • the process of the invention provides desvenlafaxine with a high purity (>99%) and richness (>99%), and yields greater than 85%.
  • the results have been obtained with moderate temperatures and reaction times, while avoiding the use of stinking reagents.
  • the purity of the obtained product can be quantitatively determined by HPLC, for example:
  • Sample preparation 0.5 mg/ml solved in an acetonitrile/water mixture (1 :1 ) v/v.
  • Retention time Desvenlafaxine (4.03 min.); Venlafaxine (6.63 min.).
  • Example 1 Reaction of Venlafaxine with triisobutylaluminium (TIBA).
  • a solution of venlafaxine (19.07 g; 68.74 mmol) in toluene (20 ml) was added to a 1.1 M solution of TIBA in toluene (187.5 ml; 206.2 mmol) while maintaining the temperature between 20 and 3O 0 C.
  • the obtained solution was maintained at reflux temperature until the amount of venlafaxine remaining is less than 1 % (about 20 hours).
  • the suspended solid was removed by filtration and washed with water (40 ml).
  • Example 2 Reaction of venlafaxine and diisobutylaluminium hydride (DIBAL).
  • a solution of venlafaxine (19.75 g; 71.2 mmol) in toluene (20 ml) was added to a 1.5 M solution of DIBAL in toluene (142 ml; 213.5 mmol) while maintaining the temperature between 20 and 3O 0 C.
  • the obtained solution was maintained at reflux temperature until the amount of venlafaxine remaining is less than 1 % (about 7 hours).
  • the suspended solid was removed by filtration and washed with water (40 ml). The liquids from the filtration and wash steps were combined and decanted.
  • the obtained solution was cooled down at room temperature and was poured slowly over water (200 ml), while maintaining the temperature below 30 0 C, to obtain an abundant precipitate.
  • the suspended solid was removed by filtration and washed with water (40 ml). The liquids from the filtration and washing steps were combined and decanted.

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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

L'invention concerne un procédé de préparation de la desvenlafaxine ou d'un sel d'addition d'acide de celle-ci pharmaceutiquement acceptable, basé sur la déméthylation de la venlafaxine par utilisation d'un aluminium-alkyle ou de composés hybrides d'aluminium-alkyle, en particulier TIBA et DIBAL.
PCT/EP2009/067041 2008-12-16 2009-12-14 Procédé de préparation de la desvenlafaxine et sels d'addition d'acide de celle-ci pharmaceutiquement acceptables Ceased WO2010079046A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES200803656A ES2343050B1 (es) 2008-12-16 2008-12-16 Procedimiento para la preparacion de desvenlafaxina y sus sales de adicion de acido farmaceuticamente aceptables.
ESP200803656 2008-12-16

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WO2010079046A1 true WO2010079046A1 (fr) 2010-07-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106928073A (zh) * 2017-03-27 2017-07-07 石家庄度恩医药科技有限公司 一种去甲文拉法辛的制备方法
US10464873B2 (en) 2017-02-09 2019-11-05 R L Finechem Private Limited Process for preparation of 1-[2-(dimethyl amino)-1-(4-hydroxyphenyl) ethyl]-cyclohexanol and salts thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026694A1 (fr) * 2000-09-29 2002-04-04 Grünenthal GmbH Derives de 6-methyl-tramadol o-substitues
WO2007120923A1 (fr) * 2006-04-17 2007-10-25 Teva Pharmaceutical Industries Ltd. O-desméthylvenlafaxine essentiellement pure et ses procédés de préparation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUP0200898A3 (en) * 1999-04-06 2005-09-28 Sepracor Inc Derivatives of venlafaxine and methods of preparing and using the same
JP4220243B2 (ja) * 2001-02-12 2009-02-04 ワイス Ｏ−デスメチル−ベンラファキシンの新規コハク酸塩
AU2008251773A1 (en) * 2007-03-15 2008-11-20 Auspex Pharmaceuticals, Inc. Deuterated venlafaxines and 0-desmetylvenlafaxines with serotoninergic and / or norepinephrinergic activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026694A1 (fr) * 2000-09-29 2002-04-04 Grünenthal GmbH Derives de 6-methyl-tramadol o-substitues
WO2007120923A1 (fr) * 2006-04-17 2007-10-25 Teva Pharmaceutical Industries Ltd. O-desméthylvenlafaxine essentiellement pure et ses procédés de préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WINTERFELDT E: "APPLICATIONS OF DIISOBUTYLALUMINIUM HYDRIDE (DIBAH) AND TRIISOBUTYLALUMINIUM (TIBA) AS REDUCING AGENTS IN ORGANIC SYNTHESIS", SYNTHESIS, GEORG THIEME VERLAG, STUTTGART, DE, 1 October 1975 (1975-10-01), pages 617 - 630, XP002030544, ISSN: 0039-7881 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10464873B2 (en) 2017-02-09 2019-11-05 R L Finechem Private Limited Process for preparation of 1-[2-(dimethyl amino)-1-(4-hydroxyphenyl) ethyl]-cyclohexanol and salts thereof
CN106928073A (zh) * 2017-03-27 2017-07-07 石家庄度恩医药科技有限公司 一种去甲文拉法辛的制备方法

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ES2343050B1 (es) 2011-06-14
ES2343050A1 (es) 2010-07-21

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