FORM-2
THE PATENTS ACT 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. A new process for preparation of O-desmethylvenlafaxine .
2. CADILA PHARMACEUTICALS LIMITED. "Cadila Corporate Campus",
Sarkhej-Dholka Road, Bhat,
Ahmedabad-382210.
Gujarat, India
Nationality: An Indian Company.
3. The following specification describes the invention.

TITLE: A new process for preparation of O-desmethylvenlafaxine

1

FIELD OF THE INVENTION
The present invention relates to a novel process for preparation of O-desmethylvenlafaxine from venlafaxine using sodium trimethylsilanethiolate .

BACKGROUND OF THE INVENTION
Venlafaxine , chemically named as (±) 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol , is an antidepressant which is described in US4761501 and in Drugs of The Future 13(9) 839-840 (1988). Its hydrochloride salt is available under the trade name Effexor®
In humans, venlafaxine is transformed by a metabolic pathway into two minor metabolites, N-desmethylvenlafaxine and N,0-didesmethylvenlafaxine and one major metabolite, O-desmethylvenlafaxine . In vivo study suggest that 0-desmethylvenlafaxine is a more potent inhibitor of norepinephrine and dopamine uptake than the parent compound venlafaxine.
US 4535186 describes the preparation of O-desmethyl venlafaxine (as per example 26) by O-debenzylation of 1-[1-(4-benzyloxyphenyl)-2-(dimethylamino)ethyl]cyclohexanol (1 gm) in 100 ml of ethanol using 10 % Pd/C (1 gm. ) and 5 ml cyclohexa 1,4-dienone to give 800 mg of solid after catalyst, solvent removal.
US 6689912 describes a process of preparing O-desmethylvenlafaxine wherein venlafaxine is O-demethylated using high molecular weight thiolate anions in high boiling solvents like PEG-400.
WO2000/59851 describes a process for preparing O-desmethylvenlafaxine wherein venlafaxine is allowed to react with diphenylphosphide in THF at reflux for overnight period. The yield was reported to be 73.8%.
US7026508 B2 describes (as per example-3) preparation of o-desmethylvenlafaxine using dodecanethiol, methanolic solution of sodium methoxide and PEG-4 00 at 190°C for about 2 hours; the temperature is lowered , followed by diluting with IPA and adjusting pH 9.5 with aqueous HCl the product is separated by suction filtration, followed by washing with IPA, toluene, IPA and water.
US 7026508 B2(in example-4) describes preparation of O-desmethyl venlafaxine from venlafaxine wherein venlafaxine is reacted with benzenethiol sodium salt in PEG-400 at 160°C for about 5 hours. The temperature was lowered followed by addition of water and pH adjustment to 3.5 with H3P04. The organic byproducts were removed by extraction

with heptanes. The product is isolated by adjusting pH to 9.5 using aqueous ammonia followed by filtration , re-slurrying in water followed by filtration and drying.
US6673838 describes a process of making succinate salt of O-desmethylvenlafaxine wherein O-desmethylvenlafaxine free base is prepared from venlafaxine using various methods.
Example 5 [of US6673838] describes reaction of venlafaxine , dodecanethiol, and ethanolic solution sodium ethoxide in a pressure vessel at 150°C and stirred for 2 days. Then the temperature is lowered and the solution is filtered. The pH of the filtrate is adjusted to 9.5 with aqueous hydrogen chloride. The compound is separated by filtration followed by washing with ethanol.
The other method (as mentioned in example-3 of US6673838) describes 0-demethylation of venlafaxine using dodecanethiol, methanolic solution of sodium methoxide and PEG-400 at 190°C.
The prior art methods described above, use high molecular weight thiolate anions for O-demethylation of venlafaxine, use very high quantity of palladium on charcoal for O-debenzylation, involve long reaction times, involve extraction steps with large volumes of solvents and produces high molecular weight sulfur compounds as byproducts making the process commercially unsuitable.
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. The paper further describes the use of sodium trimethanethiolate (Me3SiSNa) in reduction of aromatic nitro compounds to amines, conversion of nitriles to thioamides and removal of a methyl group from methoxypyridines.
The present invention involves a process of making 0-desmethylvenlafaxine from venlafaxine which is time and material efficient and produces low molecular weight sulfur compounds, which can be easily removed.

SUMMARY OF THE INVENTION
The main object of the present invention is to provide a novel and
commercially feasible process for the preparation of 0-
desmethylvenlafaxine from venlafaxine.
Another object of the invention is to provide an alternative reagent
for preparing O-desmethylvenlafaxine.
Yet another object of the invention is to avoid the use of precious
metal catalyst for preparing O-desmethylvenlafaxine from 0-benzyl
protected derivative of O-desmethylvenlafaxine.
Yet another object of the invention is to provide a process which
produces low molecular weight sulfur compounds after the demethylation
is over.
Yet another object of the invention is to provide a method with shorter
reaction times.

DETAILED DESCRIPTION OF THE INVENTION
This invention relates to derivatives of venlafaxine such as, 0-desmethyl venlafaxine- racemic or chiral isomers thereof. In accordance with the present invention, process of making 0-desmethylvenlafaxine comprises steps of demethylating a compound of Formula I to provide a compound of Formula II as described in scheme I.

As described in Scheme I, the starting material, Venlafaxine (formula I), is O-demethylated. Venlafaxine may be prepared in accordance with procedure known in the art such as described in US Pat. No.4535186
In accordance with the present invention, demethlayation is performed using a Sodium trimethylsilyl thiolate salt. Demethylation is performed by treating with trimethylsilyl halide preferably trimethylsilyl chloride with anhydrous Na2S in high boiling solvent.
The solvent is preferably ethylene glycol or ether of ethylene glycol. Ethers of ethylene glycol include, but are not limited to, ethylene glycol monoethyl ether, triethylene glycol and polyethylene glycol. Preferable solvent is an inert, high boiling solvent such as PEG- 400.
The reaction is performed at a temperature of from about 150 °C to 190 °C , preferably from about 165 °C to 175 °C .The reaction is generally allowed to progress until, not more than 1% venlafaxine remains. The reaction is complete in from about 4-8 hrs and more preferably in 5-6 hrs.
The reaction mixture is then cooled to about 65 °C -70 °C and water is added. To remove maximum organic impurity, pH of the reaction mixture is adjusted to 3.5, and organic impurities are removed using heptane and the pH of the water layer is adjusted to 9.5-10 using a base preferably aqueous ammonia, the precipitates are filtered and reslurried in water, agained filtered and the cake is washed with IPA

toluene and water. The product is dried and isolated in 75 to 85 % yield.
The present invention is illustrated by following non-limiting examples.
Example-1
Trimethylsilyl chloride (17.0 gm) , PEG 400 (25.0 ml) and Na2S (49.1 gm) were stirred for 30 minutes to give sodium trimethylsilyl thiolate. To this reaction mass, Venlafaxine (5.0 gm) in PEG-400 (20 ml) was added. The reaction mixture was heated to 160-170 °C for 7 hrs. The progress of the reaction was monitored by TLC. [TLC indicated the absence of starting material-Venlafaxine]. The reaction mass was cooled to 65-70cC. Water (100.0 ml) was charged to the reaction mass and pH was adjusted to 3.5 with H3P04. The organic byproducts were removed by extraction using heptane (25.0 ml). The pH of aqueous layer was adjusted to 9.5-10 using aq. NH3. The precipitate was collected by suction filtration, re-slurried in water (100.0 ml), separated by suction filtration. Wet cake was washed with IPA (20.0 ml), toluene (20.0 ml) and water (20.0 ml). The material was dried in vacuuo, at 55 °C for about 6 hrs. Yield = 4.7 gm 1H NMR- (DMSO: d6)
5 = 9.12 (s, br, 1H;0H), 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,0H), 3.01 (dd; J=12.3 & 8.5; 1H), 2.70 (dd, J=8.5 & 6.3; 1H) , 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 Na2S (11.3 gm) were stirred for 30 minutes to get sodium trimethylsilyl thiolate. To this reaction mixture, Venlafaxine (5.0 gm) in PEG 400 (20 ml) was added. The reaction mixture was heated to 160-170 °C for 8 hrs. The progress of the reaction was monitored by TLC. [TLC indicated the absence of starting material-Venlafaxine] . The reaction mass was

cooled to 65-70 C. Water (100.0 ml) was added to the reaction mass and pH was adjusted to 3.5 using H3P04. 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 aq. NH3. The precipitate was collected by suction filtration, re-slurried in water (100.0 ml), separated by suction filtration. Wet cake was washed with IPA (20.0 ml), toluene (20.0 ml) and water (20.0 ml). The material was dried in vacuuo, at 55 °C for about 6 hrs.
Yield = 4.1 gm
XH NMR- (DMSO: d6)
8 = 9.13 (s, br, 1H;0H), 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, 1H,0H), 3.00 (dd; J=12.3 & 8.5;
1H), 2.71 (dd, J=8.5 & 6.3; 1H) , 2.51 (dd, J=12.3 & 6.3; 1H) , 2.11 (s,
6H; 2 x Me), 0.96-1.56 (m, 10H; CycloHexanol ring).
Mass: (Q+1) = 264.4