FIELD OF INVENTION:

The present invention relates to an improved process for the preparation of 3-[(2R,3R)-l- (dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I and its pharmaceutically acceptable salt.

Formula - 1

BACKGROUND AND PRIOR ART:

The compound 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1 and its hydrochloride salt having international non proprietary name as tapentadol hydrochloride is a centrally - acting analgesic with a dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor.

The compound was first time disclosed in patent EP0693475; wherein 3-bromoanisole of Formula - II is reacted with l,l-dimethylamino-2-methylpentan-3-one of Formula - III under conditions of Grignard reaction to obtain racemic l-(dimethylamino)-3-(3- methoxyphenyl)-2-methylpentan-3-ol hydrochloride of Formula - IV. The compound of Formula - IV is converted to its base and subjected to enantiomeric separation using chiral HPLC column to obtain (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)-2- methylpentan-3-ol of Formula - V, which on chlorination using thionyl chloride forms (2S,3R)-3-chloro-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l -amine of Formula - VI. The compound of Formula - VI on reaction with zinc borohydride or tin cyanoborohydride results in the formation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2- trimethylpentan-1 -amine of Formula - VII. The compound of Formula - VII on heating with concentrated hydrobromic acid results in the compound 3-[(2R,3R)-l- (dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1. Throughout the reaction the intermediate salt formation wherever required and final hydrochloride salt preparation is done using trimethylchlorosilane The reaction sequence is as represented in scheme - 1 below.

Formula - 1

Scheme - 1

WO2004/108658 ('658) describes process for the preparation of (2R,3R)-3-(3- methoxyphenyl)-N,N,2-trimethylpentan-l -amine of Formula - VII, the penultimate intermediate to prepare tapentadol, wherein the compound (2S,3S)-l-dimethylamino-3- (3-methoxyphenyl)-2-methylpentan-3-ol of Formula - VA, is heated in acidic medium to get intermediate compound (Z,E)-(R)-[3-(3-methoxyphenyl)-2-methyl-pent-3-enyl]- dimethylamine HC1 of Formula - X, which on catalytic hydrogenation yields enantiomeric mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine of Formula - VII and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine of Formula VIIA. The required stereoisomer is separated to get (2R,3R)-3-(3- methoxyphenyl)-N,N,2-trimethylpentan-l -amine of Formula - VII. The reaction sequence is as per scheme - 2 below;

Formula - VA Formula - X

Formula -

Scheme -

WO2005/000788 ('788) describes another method of preparing tapentadol, wherein compound (2S,3S)-l-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pen tanol of Formula - VA is subjected to dehydration reaction using heterogeneous catalyst to get intermediate compound (Z,E)-(S)-[3-(3-methoxyphenyl)-2-methyl-pent-3-enyl]-dimethy l amine hydrochloride of Formula - X, which on catalytic reduction yields enantiomeric mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l -amine of Formula - VII and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l -amine of Formula - VIIA The required stereoisomer is separated to get (2R,3R)-3-(3-methoxyphenyl)-N,N,2- trimethylpentan-1 -amine Formula - VII.

WO2008/012Q46 describes another method for the preparation of tapentadol, wherein l-(3-(benzyloxy)phenyl)propan-l-one is reacted with N-Methyl-N-methylene- methaneaminium chloride in presence of acetyl chloride and solvent acetonitrile to obtain compound 1 -(3-(benzyloxy)phenyl)-3-(dimethylamino)-2-methylpropan-l-on e. The compound is resolved with L-(-)-dibenzoyltartaric acid to get (S)-l-(3- (benzyloxy)phenyl)-3-(dimethylamino)-2-methylpropan-l-one. The isolated compound is then reacted with ethyl magnesium bromide undergoing Grignard reaction to isolate (2S,3R)-3-(3-(benzyloxy)phenyl)-l-(dimethylamino)-2-methylpe ntan-3-ol, which on reaction with trifluoroacetic anhydride in acetic acid results in acetylated compound. The acetylated compound on hydrogenolysis results in the compound 3-[(2R,3R)-l- (dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1.

WO2008012047 describes yet another method for the preparation of tapentadol, wherein l-(3-methoxyphenyl)propan-l-one is reacted with dimethylamine hydrochloride and paraformaldehyde under Mannich reaction condition to get 3-(dimethylamino)-l-(3- methoxyphenyl)-2-methylpropan-l-one hydrochloride, which after treating with sodium hydroxide is reacted with (2R,3R)-0,0'-dibenzoyl tartaric acid monohydrate to get (S)-3- (dimethylamino)-l-(3-methoxyphenyl)-2-methylpropan-l-one L-(-)-dibenzoyltartarate. The dibenzoyltartrate salt is further reacted with diethylamine to isolate keto compound (S)-3-(dimethylamino)-l-(3-methoxyphenyl)-2-methylpropan-l-o ne. The keto compound is reacted with ethyl magnesium halide under Grignard condition to isolate the compound (2S,3R)-l -(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol. The hydrochloride salt of the compound (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)-2- methylpentan-3-ol on reaction with aqueous hydrochloric acid undergoes dehydration yielding the compound (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-l -amine, which after hydrogenation using homogeneous or heterogeneous catalyst results in the mixture of compound (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine having Z:E ratio of 5.5: 1. The required compound (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l -amine is separated from the mixture by making hydrochloride salt. The isolated salt is dissolved in methanesulphonic acid and treated with methionine to get the compound 3-[(2R,3R)-l- (dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I, which is isolated as hydrochloride salt.

The drawbacks of the above prior arts are,

i. it involves multistep process for synthesis of the compound of formula I;

ii. it requires the use of chiral HPLC column or chiral resolving agents to separate the required isomer;

iii. use of costly, unsafe reagents and lower yield renders the process uneconomic and industrially not useful.

Therefore, there remains a need for an improved process for preparing the compound 3- [(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I that eliminates or substantially reduces the number of steps, overcomes resolution and separation of stereoisomers, avoids chromatographic separation of required isomer and employs safe and economical reagents for the reaction.

Thus, the present inventors have come out with an improved process which ameliorates the problems in the prior art by carrying out regioselective one pot demethylation and dehydration reaction reducing the number of steps and carrying out chemical purification thus avoiding the resolution or chromatographic separation of the required isomer and use of catalyst to improve the yield, safety and economy for the preparation of the compound 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1.

The advantage of the process lies in the simultaneous demethylation and dehydration in single step maintaining the chiral purity of the intermediate compound and reducing the number of steps to prepare the compound of Formula - 1.

OBJECTIVE OF THE INVENTION:

The main objective of the present invention is to prepare 3-[(2R,3R)-l-(dimethylamino)- 2-methylpentan-3-yl]phenol of Formula - I and its pharmaceutically acceptable salt by robust, rigid and industrial friendly process. Yet another objective of the present invention is to carry out regioselective one pot demethylation and dehydration reaction of the compound (2S,3R)-l-(dimethyIamino)-3- (3-methoxyphenyl)-2-methyl pentan-3-ol of Formula - V.

Another objective of the present invention is to prepare 3-[(2R,3R)-l-(dimethylamino)-2- methylpentan-3-yl]phenol of Formula - I and its pharmaceutically acceptable salt by reduced number of steps of the reaction.

SUMMARY OF THE INVENTION:

According to the present invention there is provided a process for the preparation of 3- [(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1

Formula - 1

According to one aspect, the present invention provides a process for the preparation of 3- [(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I, comprising reacting (2S,3R)-1 -(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol of Formula - V with a mixture of methanesulfonic acid and dimethyl sulfide, which undergoes demethylation along with dehydration of tertiary hydroxyl group to yield the compound (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l -amine of Formula VIII;

Formula - VIII In another aspect of the present invention the compound of Formula VIII is reacted with an acid to get acid addition salt, which on catalytic hydrogenation in presence of solvent yields mixture of diastereomeric compounds 3-[(2R,3R)-l-(dimethylamino)-2- methylpentan-3-yl]phenol of Formula - I and 3-[(2R,3S)-l -(dimethylamino)-2- methylpentan-3-yl]phenol of Formula - 1 A;

Formula - 1 Formula - IA.

In yet another aspect of the present invention the mixture of diastereomeric compounds of Formula - I and Formula - IA on reaction with base followed by reaction with an acid yields corresponding acid addition salt which on purification in an organic solvent yields pharmaceutically acceptable salt of the compound 3-[(2R,3R)-l-(dimethylamino)-2- methylpentan-3-yl]phenol of Formula - 1.

The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the appended examples and claims.

DESCRIPTION OF THE INVENTION:

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows:

The term optically pure in the context of the present invention means the chiral isomeric purity exceeding 99.5%. The term substantially free in the context of the present invention means the stated product is free from contamination of stated impurities at least less than 0.5%, preferably less than 0.1% and most preferably less than 0.05%.

The details of one or more embodiments in the practice of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.

Accordingly the present invention provides a process for the preparation of 3-[(2R,3R)-l- (dimethylamino)-2-methylpentan-3-yl]phenol [Tapentadol] of Formula - I and its pharmaceutically acceptable salt.

Formula - 1

In an embodiment of the present invention the compound (2S,3R)-l-(dimethylamino)-3- (3-methoxyphenyl)-2 -methyl pentan-3-ol of Formula - V undergoes demethylation along with dehydration of tertiary hydroxyl group on reaction with mixture of methanesulfonic acid and dimethyl sulfide to yield the compound (2R)-3-(3-hydroxyphenyl)-N,N,2- trimeihyl-3-pentene-l -amine of Formula - VIII. The mixture of methanesulfonic acid to dimethyl sulfide is taken in the ratio of 10:3. The preferred ratio of the mixture of methanesulfonic acid and dimethyl sulfide taken for the reaction is 8:2, wherein the most preferred ratio of methanesulfonic acid to dimethyl sulfide mixture is 4: 1. The reaction is carried out at temperature in the range of -10°C to 60°C.The preferred temperature for the reaction is -5°C to 55°C, wherein the most preferred temperature for the reaction is 0°C to

55°C.

Accordingly the mixture of methanesulfonic acid and dimethyl sulfide was taken and cooled to 0°C. Charged the compound (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)- 2-methylpentan-3-ol of Formula - V slowly to the cooled mixture maintaining the temperature below 5°C. Stirred the reaction mixture and raised the temperature slowly to 55°C and maintained at 55 ± 2°C for 6 - 8 hours. The reaction was* monitored for completion on thin layer chromatography. After completion of the reaction, cooled the reaction mass to 25°C and quenched in ice cold water. Optionally if required extracted the quenched solution with toluene and separated the aqueous layer. Adjusted the pH of the aqueous layer to 9 - 10 with aqueous caustic lye solution and extracted the aqueous solution with solvent selected from n-hexane, diisopropyl ether, diethyl ether, dichloromethane, dichloroethane, ethyl acetate and methyl isobutyl ketone.The preferred solvents used for extraction are ethyl acetate, dichloromethane and methyl isobutyl ketone, wherein the most preferred solvent used is ethyl acetate. Separated the organic layer and concentrated under reduced pressure below 50°C to get the residual mass of (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l-amine of Formula - VIII.

The compound (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)-2 -methyl pentan-3-ol of Formula - V used in the present invention can be prepared as per the available prior art or by the following scheme - 3 wherein the compound 3-pentanone together with formaldehyde and dimethylamine hydrochloride undergoes stereoselective Mannich reaction in presence of L-proline and solvent n-butanol, to give (S)-l-(dimethylamino)-2- methylpentan-3-one, which on Grignard reaction with 3-bromoanisole yields the compound (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan -3-ol of Formula - V.

Formula V

Scheme - 3

In another embodiment of the present invention the compound (2R)-3-(3- hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l -amine of Formula - VIII was reacted with aqueous hydrochloric acid solution in presence of solvent selected from acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and ethyl isopropyl ketone to isolate the hydrochloride salt of (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene- 1-amine of Formula VIII. The preferred solvent used is acetone and methyl ethyl ketone, wherein the most preferred solvent used is acetone.

In another embodiment of the present invention the compound (2R)-3-(3- hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l -amine of Formula - VIII or its hydrochloride salt was taken for catalytic hydrogenation in presence of solvent at a pressure of 5 kg/cm ² to 8 kg/cm ² and temperature of 25 - 40°C to get the mixture of diastereomeric compounds of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3- yfjphenol of Formula - 1 and 3-[(2R,3S)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA. The solvent for the catalytic hydrogenation reaction is selected from methanol ethanol, n-propanol and isopropanol, wherein the most preferred solvent used for hydrogenation reaction is methanol. The catalyst used for the hydrogenation reaction is selected from platinum or palladium, preferably palladium in the form of Palladium on carbon or palladium (II) chloride. It is preferable for the invention the catalyst used in the process is Palladium on carbon. The quantity of the catalyst used is 1 wt % to 10 wt%, the preferred is 5 wt % to 10 wt %, wherein the most preferred quantity used is 10 wt % of Palladium on carbon.

Accordingly the compound (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l- amine of Formula - VIII or its hydrochloride salt was taken in solvent methanol and charged in an autoclave. The catalyst was charged and the autoclave reaction mass was flushed with nitrogen under stirring. The reaction was purged with hydrogen gas of 5.0 kg/cm ² pressure and maintained under stirring at 35 - 40°C for 3.0 hours. The reaction was filtered and filtrate concentrated under reduced pressure below 40°C to get the residual mass. Charged water and cooled the solution to 0 - 5°C and made the solution alkaline using 30% sodium carbonate solution. Extracted the aqueous solution with ethyl acetate and separated the organic layer. Concentrated the organic layer under reduced pressure below 40°C to isolate the mixture of diastereomeric compounds 3-[(2R,3R)-l- (dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I and 3-[(2R,3S)-l- (dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA. In yet another embodiment of the present invention the mixture of diastereomeric compounds of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1 and 3-[(2R,3S)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA is converted to their hydrochloride salt by suspending the residual mass in solvent acetone or mixture of acetone and methanol and purging hydrochloric acid gas till pH is 6 - 6.5. Cooled the reaction mixture to 0 - 5°C and maintained under stirring for 2 - 3 hours. Filtered the separated solid mass to get hydrochloride salt of diastereomeric compounds of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I and 3- [(2R,3S)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA.

In yet another embodiment of the present invention the hydrochloride salt of diastereomeric compounds of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I and 3-[(2R,3S)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA is purified using solvent selected from C1-C4 linear or branched alcohol either single or mixture thereof and an anti-solvent selected from ketone to isolate pure isomer 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I substantially free of its isomeric impurity of 3-[(2R,3S)-l-(dimethylamino)-2- methylpentan-3-yl]phenol of Formula - IA. The solvent C1 -C4 linear or branched alcohol used for the purification are selected from methanol, ethanol, n-propanol, isopropanol and butanol, the preferred solvent used are methanol, ethanol and isopropanol wherein the most preferred solvent used is methanol. The anti-solvent ketones used are selected from acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and ethyl isopropyl ketone. The preferred anti-solvent used is acetone and methyl ethyl ketone, wherein the most preferred anti-solvent used is acetone. The temperature used for the purification is 50°C to the reflux temperature of the alcoholic solvent used, whereas the preferred temperature for the purification is between 50°C to 90°C.

Accordingly, the mixture of hydrochloride salt of diastereomeric compounds of 3- [(2R,3R)-l-(dimethylamin0)-2-methylpentan-3-yl]phenol of Formula - 1 and 3-[(2R,3S)- l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA was taken in methanol and raised the temperature under stirring to 65°C ± 2°C. Charged antisolvent acetone slowly, maintaining the temperature at 65°C ± 2°C and maintained the reaction mass at the same temperature for 30 minutes. Cooled the reaction mass slowly to 20 - 25°C and maintained for 1.0 hour. Filtered the solid mass and washed with fresh acetone to isolate pure hydrochloride salt of compound 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3- yfjphenol of Formula - I, the undesired compound 3-[(2R,3S)-l-(dimethylamino)-2- methylpentan-3-yl]phenol of Formula - IA goes into mother liquor.

Thus after purification the present invention provides optically pure compound 3- [(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1 substantially free from the stereoisomer especially with no detectable amount of 3-[(2R,3S)-l- (dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA. The sequence of present invention is represented as shown in scheme - 4 below;

Formula I

Scheme - 4 The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.

Examples:

Example 1: Preparation of (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l- amine

In a dry flask charged methanesulfonic acid (600 ml) and cooled to 0 - 5°C. Charged dimethyl sulfide (100 ml), stirred and to the mixture charged slowly (2R,3R)-3-(3- methoxyphenyl)-N,N,2-trimethylpentan-l -amine (100 gms) maintaining temperature at 0 - 5°C. Stirred and raised the temperature of the reaction mass to 45°C. Maintained the reaction at 45 °C ± 2°C for 7 hrs. Monitored the completion of the reaction on TLC. After complete reaction cooled the reaction mass to 25 - 30°C. Quenched reaction mass in ice cold water (600ml) and extracted with toluene. Separated the aqueous layer and cooled the aqueous layer to 5°C. Adjusted pH of the aq. layer to 9 - 10 with 45% aqueous sodium hydroxide solution. Extracted the aqueous solution with ethyl acetate (3 x 100ml) and separated the organic layer. Concentrated the organic layer under reduced pressure below 50°C to get the residual mass. Charged solvent methyl ethyl ketone (210 ml) and started addition of concentrated hydrochloric acid slowly maintaining temperature at 20 - 25°C to adjust the pH of the reaction mass to 6.5 - 7.0. Maintained the reaction mass under stirring at 20-25°C for 2.0 hours. Filtered the solid separated out and washed with methyl ethyl ketone. Slurried the wet mass with petroleum ether (200 ml) and stirred for 1.0 hour. Filtered the product, washed with petroleum ether (40 ml) and dried at 50-55°C till constant weight to yield (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l-amine hydrochloride.

Yield = 46 gm (54 % yield).

Example 2: Preparation of 3-[(2R,3R)-l-(dimethyIamino)-2-methylpentan-3- yl] phenol [Tapentadol]

Charged (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l -amine hydrochloride (35.0 gm, 0.13 M) and methanol (300 ml) in a dry autoclave. Charged 10% Pd/C (50%wet, 5.0 gms). Flushed with nitrogen and pressurized the autoclave with 5.0 kg/cm ² - 6.0 kg/cm ² hydrogen gas. Maintained the reaction at 26°C ± 2°C for 3 hrs. Filtered the catalyst Pd/C from the reaction mass through hyflo bed and washed the bed with methanol (50 ml). Filtrate was concentrated under reduced pressure below 45°C and degassed to get residual oil. Charged D.M water (200 ml) and cooled the aqueous solution to 0 - 5°C. The aqueous solution made alkaline with 30% aqueous solution of sodium carbonate. Extracted the aqueous layer with ethyl acetate (3 x 100 ml). Separated the organic layer and concentrated under reduced pressure to get the compound 3-[(2R,3R)-l- (dimethylamino)-2-methylpentan-3-yl]phenol free base [Tapentadol free base].

Yield = 28 gm (93.23 % yield).

Example 3: Preparation of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3- yl]phenol hydrochloride [Tapentadol Hydrochloride]

Charged 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol (28.0 gm, 0.126 M) in acetone (85 ml). Started purging of hydrochloric acid gas maintaining the temperature at 20*25°C till the pH of the reaction mass was adjusted upto 6 - 6.5. Maintained the reaction mass under stirring for 1.0 hour at 20 - 25°C and cooled further to 0 - 5°C. Maintained the reaction mass 2.0 hrs at temperature of 0 - 5°C and filtered. The product was washed with acetone and dried at 50 - 55°C till constant weight to yield 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol hydrochloride (Tapentadol hydrochloride crude).

Yield = 28.3 gm (86.8% yield).

Example 4: Purification of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3- yl]phenol hydrochloride [Tapentadol hydrochloride]

Charged crude 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol hydrochloride (10 gms) in methanol (12 ml) and raised the temperature to reflux. Maintained the reaction mass at reflux till clear solution and started addition of anti-solvent acetone (130 ml) slowly maintaining the temperature at reflux. After the addition of anti-solvent is completed, maintained the reaction mass at reflux for 30 minutes. Cooled the reaction mass gradually to 20 - 25°C and maintained forl .O hour at 20-25°C. Filtered the product and washed with acetone. Dried the product at 50 - 55°C till constant weight to yield 3- [(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol hydrochloride (Tapentadol hydrochloride).

Yield = 6.5 gm (65.0 % yield). Example 5: Preparation of (2R)-3-(3-hydroxyphenyl)-N,N,2-triniethyl-3-pentene-l- amine

In a dry flask charged methanesulfonic acid (400 ml) and cooled to 0 - 5°C. Charged dimethyl sulfide (100 ml), stirred and to the mixture charged slowly (2R,3R)-3-(3- methoxyphenyl)-N,N,2-trimethylpentan-l -amine (100 gms) maintaining temperature at 0 - 5°C. Stirred and raised the temperature of the reaction mass to 55°C. Maintained the reaction at 55°C ± 2°C for 7 hrs. Monitored the completion of the reaction on TLC. After complete reaction cooled the reaction mass to 25 - 30°C.Quenched reaction mass in ice cold water (600 ml) and cooled to 5°C. Adjusted pH of the aq. layer to 9 - 10 with 45 % aqueous sodium hydroxide solution. Extracted the aqueous solution with ethyl acetate (3 x 100 ml) and separated the organic layer. Concentrated the organic layer under reduced pressure below 50°C to get the residual mass. Charged solvent acetone (210 ml) and started addition of concentrated hydrochloric acid slowly maintaining temperature at 20 - 25°C to adjust the pH of the reaction mass to 6.5 - 7.0. Maintained the reaction mass under stirring at 20-25°C for 2.0 hours. Filtered the solid separated out and washed with acetone. Slurried the wet mass with petroleum ether (200 ml) and stirred for 1.0 hour. Filtered the product, washed with petroleum ether (40 ml) and dried at 50-55°C till constant weight to yield (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l-amine hydrochloride.

Yield = 46 gm (54 % yield).

Example 6: Preparation of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3- yl] phenol [Tapentadol]

Charged (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l-amine hydrochloride (35.0 gm, 0.13 M) and methanol (300 ml) in a dry autoclave. Charged 10% Pd/C (50%wet, 3.5 gms). Flushed with nitrogen and pressurized the autoclave with 5.0 kg/cm ² - 6.0 kg/cm ² hydrogen gas. Maintained the reaction at 40°C ± 2°C for 3hrs. Filtered the catalyst Pd/C from the reaction mass through hyflo bed and washed the bed with methanol (50 ml). Filtrate was concentrated under reduced pressure below 45°C and degassed to get residual oil. Charged D.M water (200 ml) and cooled the aqueous solution to 0 - 5°C. The aqueous solution made alkaline with 30% aqueous solution of sodium carbonate. Extracted the aqueous layer with ethyl acetate (3 x 100 ml). Separated the organic layer and concentrated under reduced pressure to get the mixture of compound 3- [(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yI]phenol and 3-[(2R,3S)-l-(dimethyl- amino)-2-methylpentan-3-yl]phenol free base.

Yield = 28 gm (93.23 % yield).

Example 7: Preparation of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3- yl] phenol hydrochloride [Tapentadol hydrochloride]

Charged 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol (28.0 gm, 0.126 M) in mixture of acetone (84 ml) and methanol (14 ml). Started purging of hydrochloric acid gas maintaining the temperature at 20 - 25°C till the pH of the reaction mass was adjusted upto 6 - 6.5. Maintained the reaction mass under stirring for 1.0 hour at 20 - 25°C and cooled further to 0 - 5°C. Maintained the reaction mass 2.0 hrs at temperature of 0 - 5°C and filtered. The product was washed with acetone and dried at 50-55°C till constant weight to yield Mixture of compounds 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3- yl]phenol hydrochloride and 3-[(2R,3S)-l-(dimethylamino)-2-methylpentan-3-yl]phenol hydrochloride.

Yield = 19.6 gm (60.1 % yield).

Enantiomeric Purity by HPLC= 98.92%,

Diastereomeric Impurity by HPLC= 0.90%

Example 8: Purification of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3- yl]phenol hydrochloride [Tapentadol hydrochloride]

Charged crude 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol hydrochloride (10 gms) in methanol (14 ml) and raised the temperature to reflux. Maintained the reaction mass at reflux till clear solution and started addition of anti-solvent acetone (100 ml) slowly maintaining the temperature at reflux. After the addition of anti-solvent is completed, maintained the reaction mass at reflux for 30 minutes. Cooled the reaction mass gradually to 0 - 5°C and maintained for 1.0 hour at 0 - 5°C. Filtered the product and washed with acetone. Dried the product at 50 - 55°C till constant weight to yield pure compound of 3-[(2R,3R)-l -(dimethylamino)-2-methylpentan-3-yl]phenol hydrochloride (Tapentadol hydrochloride).

Yield = 7.5 gm (75.0 % yield).

Enantiomeric Purity by HPLC= > 99.50%,

Diastereomeric Impurity by HPLC= 0.04%