AN IMPROVED PROCESS FOR THE PREPARATION OF O-DESMETHYLVENLAFAX1NE.

Field of the Invention:

The present invention relates to a process for the preparation of O-desmethyl-venlafaxine by O- demethylation of venlafaxine.

Background of the invention:

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.

The publication - JOC 1993, Vol. 58, Page 4742-4744 describes use of chlorotrimethylsilane in combination with sodium sulfide as the equivalent of sodium trimethylsilanethiolate in organic reactions. It describes removal of a methyl group from methoxypyridines.

The prior art methods described above involves use of high molecular weight thiolate anions for O-demethylation of venlafaxine, use of high quantity of palladium on charcoal for O- debenzylation, involve long reaction times, involve extraction steps using large volumes of solvents and produces high molecular weight sulfur compounds as byproducts.

Therefore, there is a long-felt need to provide a better process for the preparation of O- desmethylvenlafaxine from venlafaxine which requires short reaction time and material efficient.

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 %.

Summary of the invention:

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.

Detailed description of the invention:

In accordance with the present invention, 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.

Scheme-I

or its salt Formula-ll

X= Cl , Br , I

As described in Scheme I, the starting material venlafaxine or its salt (formula I) is O- demethylated to give O-desmethylvenlafaxine. The term "O-desmethylvenlafaxine" as used herein refers to racemic mixtures or stereoisomerically pure forms of O-desmethylvenlafaxine, unless otherwise indicated.

According to present invention, 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.

In a preferred embodiment, 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.

Alternatively, after the reaction over water is added and the pH of the reaction mixture is adjusted to about 3.5 using mineral acid such as sulphuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrofluoric acid; preferably phosphoric acid. Impurities are removed by giving wash of toluene or heptane, pH of aqueous phase is adjusted to 9.5 to 10 by using a base such as carbonates, bicarbonates of alkali metals, triethyl amine, diethyl amine, preferably ammonia. The precipitate slurried in water and filtered. The cake is washed with solvent comprising group of IPA, toluene, water and dried. Thus, 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.

Example-1

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 -

10 using aqueous ammonia. The precipitates were filtered. The cake was slurried in water and filtered. The wet cake was washed with IPA (20.0 ml), toluene (20.0 ml) and water (20.0 ml).

The material was dried in vacuum at 55 ⁰ C for about 6 hrs. Product Yield is ~ 4.7 gm and Purity is - 99.08 %.

¹ H NMR- (DMSO: d ⁶ ) δ = 9.12 (s, br, 1 H;OH), 6.95 (d, br, J=8.4, 2H, arom.), 6.61 (d, br, J=8.4, 2H, arom.), 5.38 (d, br,

J=8.4, 1H ₁ OH), 3.01 (dd; J=12.3 & 8.5; 1 H), 2.70 (dd, J=8.5 & 6.3; 1 H), 2.50 (dd, J=12.3 & 6.3;

1H), 2.12 (s, 6H; 2 x Me), 0.96-1.55 (m, 10H; Cyclohexanol ring).

Mass: (Q ⁺¹ ) = 264.4

Example- 2

Trimethylsilyl chloride (6.1 gm), PEG-400 (25.0 ml) and Na ₂ S (11.3 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 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. The cake was slurried in water and filtered. Wet cake was washed with IPA (20.0 ml), toluene (20.0 ml) and water (20.0 ml). The material was dried in vacuum at 55 ⁰ C for about 6 hrs. Product Yield is -4.1 gm.

¹ H NMR- (DMSO: d ⁶ ) δ = 9.13 (s, br, 1 H;OH), 6.96 (d, br, J=8.4, 2H, arom.), 6.60 (d, br, J=8.4, 2H, arom.), 5.39 (d, br,

J=8.4, 1 H ₁ OH) ₁ 3.00 (dd; J=12.3 & 8.5; 1 H), 2.71 (dd, J=8.5 & 6.3; 1 H), 2.51 (dd, J=12.3 & 6.3;

1 H), 2.11 (s, 6H; 2 x Me), 0.96-1.56 (m, 1OH; Cyclohexanol ring).

Mass: (Q ⁺¹ ) = 264.4

Example-3

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 %.