CROSS REFERENCE TO RELATED APPLICATION This patent application claims the benefit of priority to Indian Provisional Patent Application No. 201641017954, filed on May 25, 2016, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to a novel, commercially viable and industrially advantageous process for the preparation of Tapentadol or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION • U.S. Reissue Patent No. USRE 39593 (hereinafter referred to as the US'593 patent) discloses a variety of l-phenyl-3-dimethylaminopropane compounds, processes for their preparation, pharmaceutical compositions comprising the compounds, and methods of use thereof. These compounds have the utility as analgesic active ingredients in pharmaceutical compositions. Among them, Tapentadol hydrochloride, 3-[(//?,2i?)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride, is a centrally-acting analgesic with a unique dual mode of action as an agonist at the ja-opioid receptor and as a norepinephrine reuptake inhibitor. Tapentadol hydrochloride is represented by the following structural formula:

Various processes for the preparation of Tapentadol, its enantiomfers and related
• compounds, and their pharmaceutically acceptable salts are described in U.S. Patent Nos.
. USRE 39593, US 6,344,558, US 7,417,170, US 8,138,376; US 8,877,974; US 8,853,456
and US 8,704,002; and Chinese Patent Application Nos. CN102206164A and
CN101948397A. As per the process exemplified in example 25 of the USRE39593 patent,
(-)-(lR,2R)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)-phenol hydrochloride is prepared

by the reaction of (-)-(2S,3S)-l-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride with, thionyl chloride to produce (-)-(2S,3S)-[3-chloro-3-(3-methoxyphenyl)-2-methylpentyl]-dimethyIamine hydrochloride; followed by subsequent removal of the 'CI' substituent by treatment with zinc borohydride, ziric cyanoborohydride or tin cyanoborohydride, to produce (-)-(2R,3R)-[3-(3-methoxyphenyI)-2-methyIpentyl]-dimethylamine hydrochloride; which is then converted into (-)-(lR,2R)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)-phenol hydrochloride by reaction with concentrated hydrobromic acid at reflux.
U.S. Patent No. 7,417,170 (hereinafter referred to as the '170 patent) discloses a
process for the preparation of tapentadol intermediate, (2R,3R)-3-(3-methoxyphenyl)-2-
methyl-pentyl]dimethylamine, by reacting (2S,3S)-l-dimethylamino-3-(3-
methoxyphenyl)-2-methyl-pentan-3-ol with an acid to produce a mixture of cis and trans isomers of (2R)-[3-(3-methoxyphenyl)-2-methyl-pent-3-enyl]-dimethylamine, which on catalytic hydrogenation produces a diastereomeric mixture of (2R,3R)-3-(3-methoxyphenyl)-2-methyl-pentyl]dimethylamine and (2R,3S)-3-(3-methoxyphehyl)-2-methyl-pentyljdimethylamine, followed by separation of the diastereomeric mixture to produce (2R,3R)-3-(3-methoxyphenyl)-2-methyl-pentyl]dimethylamine. The synthetic route described in the US '170 patent is depicted in Scheme-1:
U.S. Patent No. 8,138,376 (hereinafter referred to as the '376 patent), discloses a process for the preparation of tapentadol intermediate, (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamine, by reacting ' (S)-3-dimethylamino-(3-methoxyphenyl)-2-methylpropan-l-one with a Grignard reagent such as ethyl magnesium chloride, in tetrahydrofuran solvent, to produce (2S,3R)-l-(dimethylamino-3-(3-methoxyphenyl)-2-methyl-3-pentanol, followed by protecting the resulting tertiary alcohol with an acylating agent such as ethyl oxalyl chloride or acetyl chloride or trifluoro acetic anhydride in presence of 2-methyl tetrahydrofuran and subsequent hydrogenation with a transition metal catalyst such as Palladium on carbon to produce (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamine. The synthetic route described in the US'376 patent is depicted in Scheme-2:

U.S. Patent No. 8,877,974 (hereinafter referred to as the US'974 patent), discloses a process for the preparation of tapentadol hydrochloride by subjecting (2S,3R)-1-(Dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride to dehydration with aqueous hydrochloric acid to produce (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-l-amine, followed by hydrogenation under hydrogen pressure in presence of Pd/C catalyst to produce a mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine hydrochloride and (2R53S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine hydrochloride, followed by separating the. isomeric mixture using hydrogen chloride in acetone to produce (2R,3R)-3-(3-methoxyphenyl)-N3N,2-trimethylpentan-l-amine hydrochloride, which is then subjected to demethylation using methane sulfonic acid to produce tapentadol hydrochloride. The synthetic route described in the US'974 patent is depicted in Scheme-3:
U.S. Patent No. 8,853,456 (hereinafter referred to as the US'456 patent), discloses a process for the preparation of tapentadol hydrochloride by reacting (2S,3R)-1-(dimethylamino:3-(3-methoxyphenyl)-2-methylpentan-3-ol with methanesulfonic acid in presence of cone. Sulphuric acid to produce (2S,3R)-l-(dimethylamino-3-(3-methoxyphenyl)-2-methyIpentan-3-yl 4-methanesulfonate, followed by hydrogenation under hydrogen pressure in presence of 10% Pd/C catalyst using tetrahydrofuran solvent to produce (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine, which is then
subjected to demethylation using methanesulfonic acid and finally converting the tapentadol to hydrochloride salt using hydrochloric acid gas and acetone. The synthetic route described in the US'456 patent is depicted in Scheme-4:
i
US. Patent No. 8,704,002 (hereinafter referred to as the USJ002 patent) discloses a
process for the preparation of tapentadol intermediate (2R,3R)-[3-(3-methoxyphenyl)-2-
methyl-pentyl]-dimethylamine hydrochloride by the dehydration reaction of (2S,3S)-1-
dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol hydrochloride with a
heterogeneous catalyst to produce (Z3E)-(S)-[3-(3-methoxyphenyl)-2-methyl-pen-3-enyl]-
dimethylamine hydrochloride, which on catalytic hydrogenation produces a diastereomeric
mixture of (2R,3R)-[3-(3-methoxy-phenyl)-2-methyl-pentyl]-dimethyl-amine
hydrochloride and (2R,3S)-[3-(3-methoxy-phenyl)-2-methyl-pentyl]-dimethyl-amine hydrochloride, followed by separation of diastereomeric mixture to produce (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyl]-dimethylamine hydrochloride.
The processes for the preparation of Tapentadol or a pharmaceutical^ acceptable salt thereof as described in the aforementioned prior art suffer from the following disadvantages and limitations:
a; ine prior an processes involve tne use 01 nigniy corrosive reagents nice tnionyi chloride, sulphuric acid and phosphorous pentachloride;
b) the prior art processes involve the use of explosive and difficult to handle reagents such as zinc borohydride, zinc cyanoborohydride and tin cyanoborohydride;
c) the prior art processes involve the use of expensive catalytic hydrogenation reactions and noble metal catalysts such as Palladium on Carbon; and
d) the prior art processes involve the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolation /re-crystallizations.
Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of Tapentadol and its intermediates at lab scale and in commercial scale operations.
A need still remains for an improved and commercially viable process of preparing Tapentadol or a pharmaceutical^ acceptable salt thereof with high yields and high chemical and enantiomeric purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include non-hazardous conditions, environmentally friendly and easy to handle reagents, reduced reaction time periods, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of Tapentadol and its pharmaceutical^ acceptable acid addition salts in high purity and in high yield.
* SUMMARY OF THE INVENTION
The object of the present invention is to provide a novel, commercially viable and industrially advantageous process for the preparation of Tapentadol, and its intermediates, or a pharmaceutical ly acceptable salt thereof with high yield and purity.
The present inventors have surprisingly found that the Tapentadol or a pharmaceutical^ acceptable salt thereof can be prepared with high yield and purity by reducing (2S,3S)-l-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol with a hydrosilane reagent in presence of a suitable acid to produce (2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]dimethylamine hydrochloride, followed by demethylation with a suitable demethylating agent to produce Tapentadol hydrochloride.
The process for the preparation of Tapentadol or a pharmaceutically acceptable salt thereof disclosed herein has the.following advantages over the processes described in the prior art:
a) the process avoids the use of highly-corrosive reagents like thionyl chloride, sulphuric acid and phosphorous pentachloride;
b) the process avoids the use of explosive and difficult to handle reagents such as zinc borohydride, zinc cyanoborohydride and tin cyanoborohydride;
c) the process avoids the use of expensive catalytic hydrogenation reactions and noble metal catalysts such as Palladium on Carbon; and
d) the process avoids the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolation /re-crystallizations. / .
DETAILED DESCRIPTION OF THE INVENTION According to one aspect, there is provided a novel and industrially-advantageous process for the preparation of highly pure Tapentadol of formula 1:

or a pharmaceutical ly acceptable salt thereof, which comprises:
a) reacting (2S53S)-(l-dirhethylamino)-3-(3-methoxyphenyl)-2-methyl-pentan-3-oI of formula 3:
with a hydrosilane reducing reagent in presence of an acid to produce a diastereomeric mixture of desired. (2R,3R)-[3-(3-methoxyphenyl)-2-methyI-pentyI]diniethylamine of formula 2 and undesired (2R,3S)-[3-(3-methoxyphenyl)-2-methylpentyl] dimethylamine of formula 2':
b) treating the diastereomeric mixture obtained in step-(a) with hydrochloric acid in a suitable solvent to produce hydrochloride salt of the diastereomeric mixture;
c) separating the hydrochloride salt of desired (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyljdimethylamine of formula 2 from the diastereomeric mixture obtained in step-(b) using a suitable solvent; and
d) demethylating the compound of formula 2 obtained in step-(c) with a demethylating agent to produce highly pure Tapentadol of formula I or a pharmaceutically acceptable salt thereof, and optionally converting the Tapentadol or a pharmaceutical ly acceptable salt thereof into its hydrochloride salt.
Exemplary pharmaceutical ly acceptable salts of the Tapentadol of formula I include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, and tartrate. A most specific pharmaceutical^ acceptable salt of Tapentadol is hydrochloride salt.
In one embodiment, the hydrosilane reducing agent used in step-(a) is selected from the group consisting of triethylsilane, trimethylsilane, dimethyl phenyl silane, phenyl silane, triphenylsilane, trichlorosilane; and a most specific reducing agent is triethylsilane.
In another embodiment, the acid used in step-(a) is selected from the group consisting of titanium tetrachloride, aluminium chloride, aluminium bromide,
borontrifluoride, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride, zinc chloride, trifluoroacetic acid, BF3-etherate and methanesulfonic acid; and a most specific acid is titanium tetrachloride.
Exemplary solvents used in step-(a) include, but are not limited to, a hydrocarbon solvent, a chlorinated hydrocarbon solvent, and mixtures thereof.
In one embodiment, the solvent used in step-(a) is selected from the group consisting of toluene, xylene, dichloromethane, ethylene dichloride, chloroform, and mixtures thereof; and a most specific solvent is ethylene dichloride.
In another embodiment, the reaction in step-(a) is carried out at a temperature of about -10°C to reflux temperature; and specifically at a temperature of about 10°C to about reflux temperature, and more specifically at the reflux temperature. The reaction time may vary between about 1 hour to 10 hours, and more specifically about 3 hours to 5 hours.
The reaction mass containing the diastereomeric mixture obtained in step-(a) may be subjected to usual work up methods such as a washing, an extraction, a pH adjustment, an evaporation, carbon treatment, a layer separation, or a combination thereof. The resulting mass may be further isolated from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for isolating the diastereomeric mixture obtained in step-(a) is selected from the group consisting of water, acetone, methanol, -ethanol, n-propanol, isopropanol, ethyl acetate, dichloromethane, toluene, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and mixtures thereof.
Exemplary solvents used in step-(b) include, but are not limited to, an ester, a ketone, a hydrocarbon, and mixtures thereof.
In one embodiment, the solvent used in step-(b) is selected from the group consisting of ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert. butyl ketone, toluene, xylene, and mixtures thereof; and a most specific solvent is ethyl acetate or acetone.
In one embodiment, the reaction in step-(b) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, specifically at a temperature of about
25°C to the reflux temperature of the solvent used, and most specifically, at the reflux temperature of the solvent used. The reaction time may vary from about 2 hours to about 6 hours.
The reaction mass containing the hydrochloride salt of the diastereomeric mixture obtained in step-(b) may be subjected to usual work up and then isolated by the methods as described hereinabove.
The separation of diastereomers in step-(c) may be required to provide stereomers with desired optical purity. It is well known that diastereomers differ in their properties such as solubility, and thus can be separated based on the differences in their properties. The separation of the diastereomers can be performed using the methods known to the person skilled in the art. These methods include chromatographic techniques and fractional crystallization, and a preferable method is fractional crystallization.
In one embodiment, a solution of the diastereomeric mixture obtained in step-(c) is subjected to fractional crystallization.
Specific solvents used for fractional crystallization include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof; and a most specific solvent is acetone.
The fractional crystallization of desired isomer from the solution of the diastereomeric mixture can be performed by conventional methods such as cooling, partial removal of solvents, using an anti-solvent, seeding, or a combination thereof.
Fractional crystallization can be repeated until the desired chiral purity is obtained. In general, usually one or two crystallizations may be sufficient.
In one embodiment, the fractional crystallization in step-(c) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, specifically at a temperature of about 35°C to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used.
Exemplary demethylating agents used in step-(d) include, but are not limited to, hydrobromic acid, methanesulfonic acid, hydrochloric acid, trifluoroacetic acid, aluminium chloride, aluminium bromide, or a combination thereof. A most specific demethylating agent is hydrobromic acid.
The reaction mass containing the highly pure Tapentadol of formula I or a pharmaceutically acceptable salt thereof obtained in step-(d) may be subjected to usual work up methods as described hereinabove, followed by isolation and/or recrystallization from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The conversion of the Tapentadol of formula I or a pharmaceutically acceptable salt thereof into highly pure Tapentadol hydrochloride salt can be carried out as per the processes known in the art.
The (2S,3S)-(l-dimethylamino)-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol of formula 3 used as starting material in the present invention can be prepared by the methods described hereinafter in the present application, or by the methods known in the art, for example, as per the processes described in USRE39593, US 6,344,558 and WO2012/101649.
Unless otherwise specified, the compounds or intermediates prepared by the . processes described in the present application may be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
The highly pure Tapentadol, or a pharmaceutically acceptable salt thereof, obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.
In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 90°C, and specifically at about 50°C to about 85°C. The drying can be carried out for any desired time period that achieves the desired result, such a:s times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be
chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed dryer, spin flash dryer, flash dryer, and the like.
The highly pure Tapentadol or a pharmaceutically acceptable salt thereof obtained by the process disclosed herein has a total purity, includes both chemical and enantiomeric purity, of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC.
According to another aspect, there is provided a novel and industrially advantageous process for the preparation of hydrochloride salt of (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyl]dimethylamine of formula 2:

which comprises:
a) reacting (2S,3S)-(l-dimethylamino)-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol of formula 3:
with a hydrosilane reducing reagent in presence of an acid to produce a diastereomeric mixture of desired (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyl]dimethylamine of formula 2 and undesired (2R,3S)-[3-(3-methoxyphenyl)-2-methylpentyl] dimethylamine of formula 2':
treating the diastereomeric mixture obtained in step-(a) with hydrochloric acid in a suitable solvent to produce hydrochloride salt of the diastereomeric mixture; and
b) separating the hydrochloride salt.of desired (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyl]dimethylamine of formula 2 from the diastereomeric mixture obtained in step-(b) using a suitable solvent.
The preparation of the hydrochloride salt of (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyl]dimethylamine of formula 2 from the (2S,3S)-(l-dimethylamino)-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol of formula 3 as depicted in the above process steps-(a), (b) and (c) can be carried out by using the suitable reagents, methods, parameters and conditions as described hereinabove.
The following examples are given only to illustrate the present invention. However, they should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES Example 1 Preparation of (2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyI]dimethylamine hydrochloride
Step-1: Preparation of diastereomeric mixture of (2R,3R)-[3-(3-methoxyphenyl)-2-. methylpentyljdimethylamifte and (2R,3S)-[3-(3-methoxyphenyI)-2-methylpentyI] dimethylamine
Method-A: Preparation of diastereomeric mixture using ethylene dichloride solvent Ethylene dichloride (2000 ml) was added to (2S,3S)-(l-dimethylamino)-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol (100 g) and the resulting mixture was cooled to 0-5°C. Titanium tetrachloride (378 g) was slowly added to the resulting mixture and then stirred for 5-10 minutes at the same temperature. To the resulting mass, triethylsilane (176

g) was slowly added at 0-5°C. The temperature of the resulting mixture was raised to 25-
30°C and then maintained for 30 minutes at the same temperature. The reaction mass was
heated to reflux temperature and maintained for 4 hours at the same temperature. The
resulting mass was cooled to 10-15°C and then water (2000 ml) was added at the same
temperature, followed adjusting the pH of the resulting mass to 8-9 with ammonium
hydroxide at 10-15°C, and then adding dichloromethane (500 ml) at the same temperature.
The unwanted salts were filtered and washed with water (500 ml) and dichloromethane
(500 ml). The organic layer was separated from the filtrate and the aqueous layer was
extracted twice with dichloromethane (500 ml x 2). The solvent was distilled off under
reduced pressure to obtain a crude compound. The crude compound was dissolved in
toluene (300 ml), followed by the addition of a mixture of hydrochloric acid (70 ml) and
water (70 ml) at 10-15°C. The resulting mass was stirred for 10 minutes and the layers
were separated. The organic layer was washed with toluene (300 ml). The pH of the
aqueous layer was adjusted to 9-10 with dilute sodium hydroxide solution, followed by
extracting thrice with toluene (150 ml x 3). The organic layers were combined and washed
with water (150 ml), followed by the addition of activated carbon (5 g) and then stirring for
10 minutes. The resulting mass was filtered through carbon bed and washed with toluene
(50 ml). The solvent was distilled off under reduced pressure to produce 80 g of a
diastereomeric mixture of desired (2R,3R)-[3-(3-methoxyphenyl)-2-
methylpentyl]dimethylamine and undesired (2R,3S)-[3-(3-methoxyphenyl)-2-methylpentyl]dimethylamine as a residue.
Method-B: Preparation of diastereomeric mixture using dichloromethane solvent
A mixture of (2S,3S)-(l-dimethylamino)-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol (100 g) and dichloromethane (2000 ml) was cooled to 0-5°C, followed by slow addition of titanium tetrachloride (378 g) and then stirred for 5-10 minutes at the same temperature. To the resulting mass, triethylsilane (176 g) was slowly added at 0-5°C. The temperature of the reaction mass was raised to 25-30°C and maintained for 4 hours at the same temperature. To the resulting mixture, water (2000 ml) was added at below iO°C. The layers were separated and the aqueous layer was extracted with dichloromethane (1000 ml). The combined organic layers were washed with water (1500 ml) and the aqueous

layer was kept aside. The solvent was distilled off under reduced pressure to obtain crude compound. The crude compound was dissolved in toluene (300 ml), followed by the addition of a mixture of hydrochloric acid (70 ml) and water (70 ml) at 10-15°C. The resulting mass was stirred for 10 minutes and the layers were separated and the aqueous layer was washed with toluene (300 ml). The pH of the aqueous layer was adjusted to 9-10 with dilute sodium hydroxide solution and then extracted with toluene (150 ml x 3). The organic layers were combined and then washed with water (150 ml), followed by the addition of activated carbon (5 g) and then stirring for 10 minutes. The resulting mass was filtered through carbon bed and washed with toluene (50 ml). The solvent was distilled off under reduced pressure to produce 33 g of a diastereomeric mixture of desired (2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]dimethylamine and undesired (2R,3S)-[3-(3-methoxyphenyl)-2-methylpentyI]dimethylamine as a residue.
The aqueous layer (which was previously kept aside) was taken into a reaction flask and pH was adjusted to 8-9 with ammonium hydroxide at 10-15°C. To the resulting mass, dichloromethane (500 ml) was added and the salts were filtered, followed by washing with water (150 ml) and dichloromethane (150 ml). The layers were separated and the aqueous layer was extracted twice with dichloromethane (500 ml x 2). The organic layers were combined and washed with water,(500 ml). The solvent was distilled under reduced pressure to obtain crude compound. The crude compound was dissolved in dichloromethane (440 ml), followed by the addition of water (572 ml) and hydrochloric acid (132 ml), and then stirring for 10 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (250 ml). The organic layers were combined and distilled off the solvent under reduced pressure to obtain crude compound. The crude compound was dissolved in toluene (150 ml), followed by the addition of water (150 ml), and then adjusting the pH of the reaction mass to 9-10 with dilute NaOH solution. The layers were separated and the aqueous layer was extracted twice with toluene (200 ml x 2). The organic layers were combined and washed with water (150 ml). To the resulting solution activated carbon (5 g) was added and then stirred for 10 minutes. The resulting mass was filtered through activated carbon bed and washed with toluene (5 ml). The solvent was distilled off under reduced pressure to produce 17 g of diastereomeric mixture

of desired (2R,3R)-[3-(3-methoxyphenyl)-2-methyIpentyl]dimethylamine and undesired (2Rs3S)-[3-(3-methoxyphenyl)-2-methylpentyl]dimethylamine as a residue. Total weight of the obtained diastereomeric mixture: 50 g.
Step-2: Hydrochloride salt preparation:
Ethyl acetate (200 ml) was added to the diastereomeric mixture of (2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]dimethyiamine and (2R,3S)-[3-(3-methoxyphenyl)-2-methylpentyl]dimethylamine (50 g, obtained in Step-1) at 25-30°C and then stirred for 10 minutes at the same temperature. Activated carbon (2 g) was added to the resulting mixture at 25-30°C and stirred for 10-15 minutes at the same temperature. The resulting mixture was filtered and washed with ethyl acetate (25 ml). To the resulting filtrate, a saturated solution of hydrochloric acid in ethyl acetate (130 ml) was slowly (drop-wise) added for a period of 2-3 hours and then stirred for 30 minutes at 25-30°C. The resulting mass was refluxed for 1 hour and then cooled to 25-30°C, followed by stirring for 30 minutes at the "' same temperature. The resulting mass was filtered and washed with ethyl acetate (75 ml) to produce 30 g of the mixture (2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl] dimethylamine hydrochloride salt and (2R,3S)-[3-(3-methoxyphenyI)-2-methylpentyljdimethylamine hydrochloride salt.
Step-3: Separation of Diastereomers:
Acetone (110 ml) was added to a mixture of (2Rs3R)-[3-(3-methoxyphenyl)-2-methylpentyljdimethylamine hydrochloride and (2R,3S)-[3-(3-methoxyphenyl)-2-methylpentyljdimethylamine hydrochloride (30 g, obtained in step-2) at 25-30°C. The resulting mixture was heated to reflux temperature and maintained for 1 hour at the same temperature. The reaction mass was cooled to 25-30°C and then stirred for 30-45 minutes at the same temperature. The resulting mass was filtered and washed with acetone (36.5 ml) to produce 20 g of (2R?3R)-[3-(3-methoxyphenyl)-2-methylpentyl]dimethylamine hydrochloride (Purity by HPLC: 97.0%).

Example 2
Preparation of (lR,2R)-3-(3-dimethylamino-l-ethyl-2-methyIpropyl)phenol
hydrochloride (Tapentadol hydrochloride) Step-1: Preparation of Tapentadol free base
(2R53R)-[3-(3-methoxyphenyl)»2-methyIpentyl]dimethyIamine hydrochloride (20 g), hydrobromic acid (42 ml) and hydrochloric acid (18 ml) were taken into a reaction flask at 25-30°C. The resulting mixture was heated to 100-105°C and maintained for 10 hours at the same temperature. After completion of the reaction, the reaction mass was initially cooled to 25-30°C and then subsequently cooled to 0°C, followed by stirring for 1 hour at the same temperature. The product obtained was filtered to produce 27.5 g of the wet compound. To the resulting wet compound, water (120 ml) was added at 25-30°C and then stirred for 10 minutes at the same temperature. After complete dissolution, ethyl acetate (55 ml) was added and the pH of the reaction mass was adjusted to 9-9.5 with ammonia solution (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (55 ml x 2). The organic layers were combined and washed, with water (40 ml). Activated Carbon (1.5 g) was added to the resulting organic layer and stirred for 10 minutes at 25-30°C. The resulting mixture was filtered through carbon bed and washed with ethyl acetate (15 ml). The filtrate was distilled under vacuum at 80°C to obtain a residue. To the residue, ethanol (25 ml x 2) was added and the solvent was distilled off to obtain 15.5 g of Tapentadol free base (Purity by HPLC: 98.0%).
Step-2: Preparation of Tapentadol hydrochloride
Ethanol (37.5 ml) was added to the Tapentadol free base (15 g, obtained in step-1) at 25-30°C and then stirred for 10 minutes at the same temperature. After complete dissolution, Activated Carbon (1 g) was added and then stirred for 10 minutes. The resulting mixture was filtered and washed with ethanol (7.5 ml). The filtrate was cooled to 0-5°C, followed by adjusting the pH to 1 with ethanolic HC1 (22.5 ml) at 0°C. The resulting mass was stirred for 30 minutes at 0-5°C. The separated solid was filtered, washed with chilled ethanol (15 ml) and then dried the material at 110-115°C for 2-3 hours to produce 10 g of crude Tapentadol hydrochloride (Purity by HPLC: 99.5%).

Step-3: Purification of crude Tapentadol hydrochloride:
Crude Tapentadol hydrochloride (10 g) was added to isopropyl alcohol (100 ml) and then heated to reflux temperature while stirring, followed by stirring the reaction mass for 30 minutes at the same temperature. The resulting mass was cooled to 0-5°C and then stirred for 30 minutes at the same temperature. The separated solid was filtered, washed with cold isopropyl alcohol (10 ml) and then dried the material at 40-45°C for 4-5 hours to produce 9 g of pure Tapentadol hydrochloride (Purity by HPLC: 99.9%).

We claim:
1. A process for the preparation of highly pure Tapentadol of formula 1:
or a pharmaceutical^ acceptable salt thereof, which comprises:
a) reacting (2S,3S)-(l-dimethylamino)-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol of
formula 3:
with a hydrosilane reducing reagent in presence of an acid to produce a diastereomeric mixture of desired (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyljdimethylamine of formula 2 and undesired (2R,3S)-[3-(3-methoxyphenyl)-2-methylpentyl] dimethylamine of formula 2':
b) treating the diastereomeric mixture obtained in step-(a) with hydrochloric acid in a .
suitable solvent to produce hydrochloride salt of the diastereomeric mixture;
c) separating the hydrochloride salt of desired (2R,3R)-[3-(3-methoxyphenyl)-2-
. methyl-pentyi]dimethylamine of formula 2 from the diastereomeric mixture
obtained in step-(b) using a suitable solvent; and
d) demethylating the compound of formula 2 obtained in step-(c) with a
demethylating agent to produce Tapentadol of formula I or a pharmaceutical^
acceptable salt thereof, and optionally converting the Tapentadol or a
pharmaceuticaliy acceptable salt thereof obtained into highly pure Tapentadol
hydrochloride salt.
2. The process of claim 1, wherein the pharmaceuticaliy acceptable salt of the Tapentadol of formula I is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fiimarate, benzenesulfonate, toluenesulfonate, citrate, and tartrate.
3. The process of claim 1, wherein the hydrosilane reducing agent used in step-(a) is selected from the group consisting of triethylsilane, trimethylsilane, dimethyl phenyl silane, phenyl silane, triphenylsilane, trichlorosilane; wherein the acid used in step-(a) is selected from the group consisting of titanium tetrachloride, aluminium chloride, aluminium bromide, borontrifluoride, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride, zinc chloride, trifluoroacetic acid, BF3-etherate and methanesulfonic acid; wherein the solvent used in step-(a) is selected from the group consisting of toluene, xylene, dichloromethane, ethylene dichloride, chloroform, and mixtures thereof; wherein the solvent used in step-(b) is selected from the group consisting of ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert. butyl ketone, toluene, xylene, and mixtures thereof; and wherein the demethylating agent used in step-(d) is selected, from the group consisting of hydrobromic acid, methanesulfonic acid, hydrochloric acid, . trifluoroacetic acid, aluminium chloride, aluminium bromide, or a combination thereof.
4. The process of claim 3, wherein the hydrosilane reducing agent used in step-(a) is triethylsilane; wherein the acid used in step-(a) is titanium tetrachloride; wherein the
5. solvent used in step-(a) is ethylene dichloride; wherein the solvent used in step-(b) is ethyl acetate or acetone; and wherein the demethylating agent used in step-(d) is hydrobromic acid.
5. The process of claim 1, wherein the separation of hydrochloride salt of (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyl]dimethylamine of formula 2 in step-(c) is carried out by fractional crystallization using a solvent selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof.
6. The process of claim 5, wherein the solvent used for fractional crystallization is acetone.
7. A process for the preparation of (2R53R)-[3-(3-methoxyphenyl)-2-methyl-pentyl]dimethylamine hydrochloride salt of formula 2:
which comprises:
a) reacting (2S,3S)-(1 -dimethylamino)-3-(3-methoxyphenyl)-2-methyl-pentan-3-oI of formula 3:
with a hydrosilane reducing reagent in presence of an acid to produce a . diastereomeric mixture of desired (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyljdimethylamine of formula 2 and undesired (2R,3S)-[3-(3-methoxyphenyl)-2-methylpentyl] dimethylamine of formula 2':
t
b) treating the diastereomeric mixture obtained in step-(a) with hydrochloric acid in a suitable solvent to produce hydrochloride salt of the diastereomeric mixture; and
c) separating the hydrochloride salt of desired (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyl]dimethylamine of formula 2 from the diastereomeric mixture obtained in step-(b) using a suitable solvent.
The process of claim 7, wherein the hydrosilane reducing agent used in step-(a) is selected from the group consisting of triethylsilane, trimethylsilane, dimethyl phenyl silane, phenyl silane, triphenylsilane, trichlorosilane; wherein the acid used in step-(a) is selected from the group consisting of titanium tetrachloride, aluminium chloride, aluminium bromide, borontrifluoride, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride, zinc chloride, trifluoroacetic acid, BF3-etherate and methanesulfonic acid; wherein the solvent used in step-(a) is selected from the group consisting of toluene, xylene, dichloromethane, ethylene dichloride, chloroform, and mixtures thereof; wherein the solvent used in step-(h) is selected from the group consisting of ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert. butyl ketone, toluene, xylene, and mixtures thereof; and wherein the separation of the hydrochloride salt of desired (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyI]dimethylamine of formula 2 in step-(c) is carried out by fractional crystallization using a solvent selected from the group consisting of

acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof.
9. The process of claim 8, wherein the hydrosilane reducing agent used in step-(a) is triethylsilane; wherein the acid used in step-(a) is titanium tetrachloride; wherein the solvent used in step-(a) is ethylene dichloride; and wherein the solvent used in step-(b) is ethyl acetate or acetone.
10. The process of claim 8, wherein the solvent used for fractional crystallization in step-(c) is acetone.