DESC:A NOVEL PROCESS FOR THE PREPARATION OF 1-PHENYL-3-AMINOPROPANE DERIVATIVES

FIELD OF THE INVENTION
The present invention relates to process for preparation of 1-phenyl-3-aminopropane derivatives, stereospecific isomers and/or pharmaceutically acceptable salts thereof. The present invention also relates to novel intermediates for preparation of 1-phenyl-3-aminopropane derivatives, stereospecific isomers and/or pharmaceutically acceptable salts thereof. Further, the present invention relates to a process for the preparation of Tapentadol and/or its pharmaceutically acceptable salts via novel intermediate.

BACKGROUND OF THE INVENTION
The treatment of chronic and non-chronic states of pain is of great importance in medicine. This is reflected in the large number of publications. U.S. Patent No. 6248737 discloses an active compound class of 1-phenyl-3-aminopropane derivatives compounds, with an excellent analgesic activity and very good tolerability of these substances as pharmaceutical active ingredients, in particular Tapentadol.

Tapentadol, is chemically known as 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2­
methylpropyl]phenol or 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol. Tapentadol was approved as hydrochloride salt by the FDA in November 2008 for the treatment of moderate to severe acute pain. It 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.

Tapentadol and its analogue compounds were disclosed in U.S. Patent No. RE39593. The US ‘593 also discloses a process for the preparation of Tapentadol which involves reaction of 3-bromoanisole and 1-dimethylamino-2-methylpentane-3-one under conditions of Grignard reaction to form diastereomeric mixture of 1-dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol, which is then subjected for separation of two enantiomeric pairs by precipitation and using a chiral HPLC column to provide (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. The resolved intermediate is then chlorinated, reduction with zinc borohydride or tin cyanoborohydride and finally demethylated by heating with concentrated hydrobromic acid to form 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol.

U.S. Patent No. 6,653,508 B2; U.S. Patent No. 7,417,170 B2; U.S. Patent No. 7,649,114 B2 and U.S. Patent No. 8,410,176 B2; U.S. Patent Application No. 2006/0167318 Al and US 2012/0232306 A1; International (PCT) publications; WO 2011/080756 Al, WO 2011/026314 A1, WO 2011/092719 A2, WO 2008/012046 Al, WO 2008/012047 Al, WO 2008/012283 Al, WO 2011/0107876 A2 and WO 2013/185928; Chinese application No. 102936205 disclose the various alternative processes for the preparation of 3-amino-2-benzyl-l-phenylpropane derivatives, intermediates and separation of stereo isomeric N,N-dialkylamino-2-alkyl-3-hydroxy-3-pheny]alkanes, i.e. tapentadol and their analogue compounds.

CN 102320984 discloses a process for the preparation of Tapentadol hydrochloride, which involves reaction of 1-(3-methoxyphenyl)-1-propanone with N,N,N',N'- tetramethylmethanediamine to provide 3-dimethylamino-1-(3-methoxyphenyl)-2- methyl-1-propanone, which is treated with L-(-) - dibenzoyl tartaric acid monohydrate to provide (S)-3-(dimethylamino)-1- (3-methoxyphenyl) -2 - methyl-propan-1 - one L-(-) - dibenzoyl tartaric acid salt, which is converted to (R)-3-(dimethylamino)-1 - (3-methoxyphenyl) -2 - methyl-propan-1-one, which is then reacted with ethyl triphenylphosphonium bromide in presence of methyl t-butyl ether and potassium t-butoxide to provide (R)-3-(3-methoxyphenyl)-N,N,2-trimethyl-pent-3-en-1-amine, which is finally converted to Tapentadol hydrochloride. However, the process involves treatment of stereoisomer, obtained after resolution step, with strong base during the reaction with Wittig reagent and its work-up, in which stereoisomer converts to racemic compound.

The prior art processes involve use of one or the other of expensive reagents, hazardous chemicals, number of reaction steps, and impure intermediates, which makes the process expensive and unsafe for the industrial scale-up.

Therefore, there is a need to develop an alternative process for the preparation of the 1-phenyl-3-aminopropane derivative such as Tapentadol or acid addition salts thereof, which is commercially viable and which has advantage over the processes, described in the prior arts.

SUMMARY OF THE INVENTION
The present invention provides novel intermediates and process for the preparation of 1-phenyl-3-aminopropane derivatives. Further, the present invention provides a process for the preparation of Tapentadol and/or pharmaceutically acceptable salts thereof.

In an aspect, the present invention provides a process for preparing a (2R, 3R)-compound of formula-(I)
(I)
or stereospecific isomers and/or its pharmaceutically acceptable salts thereof,
wherein R1 is a hydrogen atom or a hydroxyl-protecting group, independently selected from the group consisting of C1-C10 straight or branched chain alkyl, C2-C10 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or heterocycle, tri-C1-4 alkyl silyl, phenyl di C1-4 alkyl and diphenyl mono C1-4 alkyl silyl; wherein aryl or alkyl-aryl group is optionally substituted by a halogen atom; R2 and R3 are amino-protecting group, independently selected from the group consisting of hydrogen, C1-C10 straight or branched chain alkyl, C2-C10 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or heterocycle; wherein aryl or alkyl-aryl group is optionally substituted by a halogen atom, which comprises:
a) reaction of compound of formula IV with Wittig reagent to provide a compound of formula V;

b) resolution of the compound of formula V using resolving agent A to provide compound of formula VI;

c) reaction of the compound of formula VI with a base to provide compound of formula VII;

d) reduction of the compound of formula VII with metal catalyst to provide compound of formula I.
wherein R1, R2 and R3 are the same as defined above; A is optically active acid, selected from tartaric acid or its derivatives such as (-)-O,O-dibenzyl-L-tartaric acidmonohydrate, D-(-)-tartaric acid, L-(+)-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (-)-dibenzoyl–L-tartaric acid, (+)-dibenzoyl-D-tartaric acid or S-naproxen or mixture thereof.

In another aspect, the present invention provides a novel intermediate of formula (VI) or its salts:

wherein R1, R2, R3 and A are the same as described above.

In another aspect, the present invention provides a process for preparation of novel intermediate of formula (VI) or its salts:

wherein the method comprises:
a) reaction of compound of formula IV with Wittig reagent to provide a compound of formula V;

b) resolution of the compound of formula V using resolving agent A to provide compound of formula VI;
,
wherein, R1, R2, R3 and A are the same as described above.

In another aspect, the present invention provides a process for the preparation of Tapentadol of formula Ia:

or its pharmaceutically acceptable salts, comprising:
a) reaction of 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methypropan-1-one of formula IVa with Wittig reagent in the presence of organic solvent to provide (RS)-3-(3-methoxyphenyl)-N,N, 2-trimethylpent-en-1-amine;

b) resolution of the compound of step a) with chiral reagent of tartaric acid to provide salt of (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine with chiral reagent;
c) reaction of the salt of step b) with a base to provide (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine of formula VIIa;

d) reduction of the compound of step c) with metal catalyst and ammonium formate to provide (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan-1-amine of formula Ib or its salts; and,

e) demethylation of the compound of step d) using an acid to provide Tapentadol or its pharmaceutically acceptable salts.

In another aspect, the present invention provides a process for the preparation of intermediate of Tapentadol, (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine, which comprises:
a) reaction of 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methypropan-1-one with Wittig reagent in the presence of ether to provide (RS)-3-(3-methoxyphenyl)-N,N, 2-trimethylpent-en-1-amine;
b) resolution of the compound of step a) with (-)-O,O- dibenzoyl-L-tartaric acid to provide (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine (-)-O,O- dibenzoyl-L-tartaric acid salt; and
c) reacting the salt of step b) with an amine to provide (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine.

In another aspect, the present invention provides a process for preparation of intermediate of Tapentadol, 2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan-1-amine or its salt, which comprises reduction of (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine with metal catalyst and ammonium formate to provide (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan-1-amine or its salts.

DETAILED DESCRIPTION OF THE INVENTION
The term "substantially pure" as used herein, unless otherwise defined, refers to Tapentadol, an intermediate thereof, or a salt thereof that contains purity greater than 99%.

The intermediates and starting materials of the present invention may be produced and used as free bases or its salts.

The term Tapentadol as used herein refers to all polymorphic forms of tapentadol or pharmaceutically acceptable salts thereof, for example polymorphs of crystalline form, or hydrates, and solvates thereof.

The salt or pharmaceutically acceptable salt as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate, tartrate and the like.

In an aspect, the present invention provides a process for preparing a compound of formula- (I), its stereospecific isomers or pharmaceutically acceptable salts thereof,
(I)
wherein R1 is a hydrogen atom or a hydroxyl-protecting group, independently selected from the group consisting of C1-C10 straight or branched chain alkyl, C2-C10 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or heterocycle, tri-C1-4 alkyl silyl, phenyl di C1-4 alkyl and diphenyl mono C1-4 alkyl silyl; wherin aryl or alkyl-aryl group is optionally substituted by a halogen atom; R2 and R3 are amino-protecting group, independently selected from the group consisting of hydrogen, C1-C10 straight or branched chain alkyl, C2-C10 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or heterocycle; wherin aryl or alkyl-aryl group is optionally substituted by a halogen atom; which comprises:
a) reaction of the compound of formula (IV) with a Wittig reagent to form a compound of formula (V):

b) resolution of the compound of formula V with resolution agent-A to provide compound of formula (VI):

wherein R1, R2 and R3 are the same as defined above; A is optically active acid, which is selected from the group consisting of (-)-O,O-dibenzyl-L-tartaric acidmonohydrate, D-(-)-tartaric acid, L-(+)-tartaric acid, S-naproxen, (-)-di-p-toluoyl-L-tartaric acid, (-)-dibenzoyl–L-tartaric acid, (+)-dibenzoyl-D-tartaric acid or mixture of thereof;
c) reaction of the compound of formula (VI) with base in organic solvent, to provide R-isomer of formula (VII)

d) reduction of the compound of formula VII with metal catalyst to provide compound of formula I.

The overall process is represented in the following scheme I:

The Wittig reaction involves reaction of compound of formula (IV) with a Wittig reagent:
The compound of formula IV can be prepared by condensation reaction between 1-phenylpropan-1-one and dimethyl amine or its salt in the presence of paraformaldehyde and acid such as hydrochloric acid in suitable organic solvent such as alcohol, for example, isopropyl alcohol.

The Wittig reaction is conducted between compound of formula (IV) and Wittig reagent in the presence of base in suitable organic solvent.

The reaction is carried out with the suitable Wittig reagent such as ethyltriphenylphosphonium halides in the presence of suitable base. More preferably the wittig reagent is selected from ethyltriphenylphosphonium chloride and ethyltriphenylphosphonium bromide. The base is selected from metal alkoxides or metal carbonates or metal bicarbonates. The metal alkoxides are selected from sodium methoxide, potassium t-butoxide, lithium t-butoxide, sodium t-butoxide, alluminium t-butoxide and the like; the metal carbonates are selected from sodium carbonate, potassium carbonate and the like; the metal bicarbonates are selected from sodium bicarbonate or potassium bicarbonate and the like.

The Wittig reaction may be carried out in presence of organic solvent which includes but are not limited to ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, and the like; haloalkanes such as dichloromethane, chloroform and the like; and mixtures thereof. Preferably, the organic solvent is selected from diisopropyl ether, dichloromethane. More preferably the solvent is diisopropyl ether.

The reaction may be carried out at a temperature of about 10°C to about 120°C. Preferably, the reaction is carried out at a temperature of about 20°C to about 40°C. The reaction may be carried out for a period of about 2 hours to about 5 hours. Preferably the reaction is carried out for about 2 hours to 3 hours.

The resolution step involves the reaction between the compound of formula (V) with resolution agent-A in suitable organic solvents.

The reaction is carried out with a suitable resolution agent-A which includes, but is not limited to optically active acid selected from the group consisting of S-naproxen, tartaric acid and its derivatives (-)-O,O-dibenzyl-L-tartaric acidmonohydrate, D-(-)-tartaric acid, L-(+)-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (-)-dibenzoyl –L-tartaric acid, (+) – dibenzoyl – D-tartaric acid and hydrates thereof. Preferably the resolution agent-A is (-)-O,O-dibenzyl-L-tartaric acidmonohydrate.

According to the present invention, the compound of formula (VI) is obtained by the reaction step-b as described above, and may be isolated as solid.

The resolution step is carried out in presence of organic solvent which is selected, but is not limited to alcoholic solvents such as branched or straight chain C1-C4 alcohols, selected from methanol, ethanol, isopropyl alcohol, and the like; esters like ethyl acetate, butyl acetate, and the like; ketones like acetone, methyl ethyl ketone, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, and the like; Haloalkanes such as dichloromethane, chloroform and the like; and mixtures thereof. Preferably the solvent is ethyl acetate.

The reaction is carried out at a temperature of about 10°C to about 150°C. Preferably, the reaction is carried out at a temperature of about 55°C to about 75°C. The reaction is carried out for a period of about 2 hours to about 12 hours. Preferably the reaction is carried out for about 3 hours to about 5 hours.

After completion of reaction, the reaction mixture is cooled to about 0°C to 30°C and filtered. The filtered solid product is washed with organic solvent and dried. The product obtained can be used in step-(c) as described in above detailed description.

The reaction step-c is desaltification reaction which involves reaction between the compound of formula (VI) and base in suitable organic solvents.

The reaction is carried out with a suitable base which includes, but is not limited to organic or inorganic base like ammonia, alkyl amine, metal alkoxides, metal carbonates. More particularly, the base includes, but is not limited to alkyl amine such as diethyl amine, triethyl amine, dimethyl amine, methyl ethyl amine, pyridine, and the like; alkali metal or alkali earth metal alkoxides such as sodium methoxide, potassium t-butoxide, lithium t-butoxide, sodium t-butoxide, alluminium t-butoxide and the like; alkali metal carbonate such as sodium carbonate, potassium carbonate, and the like; alkali metal bicarbonate agents such as sodium bicarbonate, potassium bicarbonate and the like. Preferably the base is weak base such as diethyl amine.

The reaction step-c is carried out with the suitable organic solvent preferably selected, but not limited to alcoholic solvents such as branched or straight chain C1-C4 selected from methanol, ethanol, isopropyl alcohol, and the like; esters like ethyl acetate, butyl acetate, and the like; ketones like acetone, methyl ethyl ketone, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, and the like; Haloalkanes such as dichloromethane, chloroform and the like; and mixtures thereof. A preferred solvent is ethyl acetate.

The reaction is carried out at a temperature of about 10°C to about 150°C. Preferably the reaction is carried out at about 20°C to about 40°C. The reaction is carried out for a period of about 2 hours to about 8 hours. Preferably the reaction is carried out for about 4 hours to about 5 hours.

The step of reduction involves, reaction between an R-isomer of compound of formula (VII) with metal catalyst /carbon in the presence of hydrogen or ammonium formate, further optionally deprotection of hydroxyl group with suitable acid/s or acid derivatives in organic solvents. The reaction may takes place in an aqueous or non-aqueous medium.

The reaction is carried out with a suitable metal catalyst which includes, but is not limited to metal or non-metal catalyst such as iron, zinc, magnesium, palladium, platinum, triphenylphosphine, and the like. Preferably the reducing agent is palladium.

The reaction is carried out in presence of an organic solvent preferably selected, but not limited to alcoholic solvents such as branched or straight chain C1-C4 alcohols selected from methanol, ethanol, isopropyl alcohol, and the like; aprotic solvents like water, pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane, carbon tetrachloride, freon-11, toluene, triethyl amine, carbon disulfide, diisopropyl ether, diethyl ether (ether), t-butyl methyl ether (MTBE), chloroform, ethyl acetate, 1,2-dimethoxyethane (glyme), 2-methoxyethyl ether (diglyme), tetrahydrofuran (THF), methylene chloride, pyridine (Py), 2-butanone (MEK), acetone, hexamethylphosphoramide, N-methylpyrrolidinone, nitromethane, dimethylformamide, acetonitrile and the like; and mixtures thereof. More preferably, the organic solvent is methanol.

The reaction is carried out at a temperature of about 0°C to about 150°C. Preferably the reaction is carried out at about 20°C to about 40°C. The reaction is carried out for a period of about 1 hour to about 5 hour. Preferably the reaction is carried out for about 4 hour to about 5 hour. The reduction may also be conducted using Pd on carbon in presence of hydrogen gas.

The reaction step of hydroxyl deprotection is carried out with a suitable acid/s or acid derivatives, which includes, but is not limited to organic acid or mineral acid such as acetic acid, lactic acid, formic acid, citric acid, oxalic acid, uric acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, methane sulphonic acid, boric acid, hydrofluoric acid, hydrobromic acid and perchloric acid. Preferably, the acid is selected from methane sulphonic acid, or acetic acid.

The reaction step of hydroxyl deprotection is carried out with or without presence of DL-methionine. Absence of the DL-methionine reaction will proceed with longer times.

After completion of the reaction, the reaction mass may be diluted with water and then pH adjusted to 10-12 by using alkali solution. Then, the reaction mass may be extracted into organic solvent and distilled out completely till oily mass obtained, which is used for salt preparation directly using conventional methods by using suitable pharmaceutically acceptable acid.

In another aspect, the present invention provides a novel intermediate of formula (VI) or its salts:

wherein R1, R2, R3 and A are the same as described above.

In an embodiment, the compound of formula VI is the compound of formula VIa:
DBTA: (-)-O,O-dibenzyl-L-tartaric acid or its monohydrate.

In another aspect, the present invention provides a process for preparation of novel intermediate of formula (VI) or its salts:

wherein the method comprises:
a) reaction of compound of formula IV with Wittig reagent to provide a compound of formula V;

b) resolution of the compound of formula V using resolving agent A to provide compound of formula VI;
,
wherein, R1, R2, R3 and A are the same as described above.

The Wittig reaction is conducted by using Wittig reagent such as ethyltriphenylphosphonium halides in the presence of base such as metal alkoxides or metal carbonates or metal bicarbonates in suitable organic solvent such as ether, haloalkanes.

The resolution of the compound of formula (V) is performed by using resolving agent-A includes optically active acid such as tartaric acid and its derivatives in suitable organic solvents such as alcoholic solvent, ketone, ether, ester, haloalkane or mixture thereof.

In another aspect, the present invention provides a process for the preparation of tapentadol of the following formula (Ia):

or pharmaceutically acceptable acid addition salt thereof, comprising:
a) reaction of 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methypropan-1-one of formula IVa with Wittig reagent in the presence of organic solvent to provide (RS)-3-(3-methoxyphenyl)-N,N, 2-trimethylpent-en-1-amine;

b) resolution of the compound of step a) with chiral reagent of tartaric acid or its derivative to provide salt of (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine with chiral reagent;
c) reaction of the salt of step b) with a base to provide (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine of formula VIIa;

d) reduction of the compound of step c) with metal catalyst and ammonium formate to provide (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan-1-amine of formula Ib or its salt; and,

e) demethylation of the compound of step d) by using an acid to provide Tapentadol or its pharmaceutically acceptable salt.

The reaction step-a involves reaction of compound of formula (IVa) with a Wittig reagent in presence of ether solvent.

The Wittig reagent is selected from ethyltriphenylphosphonium chloride and ethyltriphenylphosphonium bromide. The reaction may be conducted in the presence of base, such as potassium t-butoxide.

The Wittig reaction is carried out in presence of ether solvent such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, and the like. Preferably the solvent is diisopropyl ether.

The reaction may be carried out at a temperature of about 10°C to about 120°C. Preferably, the reaction is carried out at a temperature of about 20°C to about 40°C. The reaction may be carried out for a period of about 2 hours to about 5 hours. Preferably the reaction is carried out for about 2 hours to 3 hours.

After completion of the reaction, the reaction mass may be filtered, the filtrate combined with water and then pH adjusted to less than 1 with acid such as hydrochloric acid to obtain aqueous layer. The aqueous layer may be basified with ammonia and the reaction product extracted with an organic solvent. The organic layer may be subjected for complete distillation under vacuum to give oily product that may be subjected for solid isolation or used directly for further steps.

The reaction step-b is resolution, the reaction between the compound of formula (Va) with resolution agent-A in suitable organic solvents.

The reaction is carried out with a suitable resolution agent-A which includes, but is not limited to optically active acid selected from the group consisting of S-naproxen, tartaric acid and its derivatives, (-)-O,O-dibenzyl-L-tartaric acidmonohydrate, D-(-)-tartaric acid, L-(+)-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (-)-dibenzoyl –L-tartaric acid, (+) – dibenzoyl – D-tartaric acid and hydrates thereof. Preferably the resolution agent-A is (-)-O,O-dibenzyl-L-tartaric acid monohydrate.

The resolution step is carried out in presence of organic solvent which includes but are not limited to ester like ethyl acetate, butyl acetate, and the like. Preferably the solvent is ethyl acetate. The reaction is carried out at a temperature of about 55°C to about 75°C for a period of about 3 hours to about 5 hours.

After completion of reaction, the reaction mixture is cooled to about 0°C to 30°C, filtered and dried to use in further steps directly without purification.

The reaction step-c involves reaction between the compound of formula (VIa) and base in suitable organic solvents. The base is selected from ammonia, alkyl amine, metal alkoxides, metal carbonates. More particularly, the base includes, but is not limited to alkyl amine such as diethyl amine, triethyl amine, dimethyl amine, methyl ethyl amine, pyridine, and the like; alkali metal or alkali earth metal alkoxides such as sodium methoxide, potassium t-butoxide, lithium t-butoxide, sodium t-butoxide, alluminium t-butoxide and the like, preferably the metal alkoxide is potassium t-butoxide; alkali metal carbonate, alkali metal bicarbonate agents such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. Preferably the base is weak base such as diethyl amine.

The reaction step-c is carried out in presence of ester solvent like ethyl acetate, butyl acetate, and the like. The resolution step and desaltification step may be performed in same solvent.

The reaction is carried out at a temperature of about 20°C to about 40°C for a period of about 4 hours to about 5 hours.

After completion of reaction, the reaction mixture may be cooled to about 0°C to 30°C, filtered and washed with organic solvent and dried to use for further steps directly.

The reaction step-d is reduction reaction between an R-isomer of compound of formula (VII) with metal catalyst /carbon in the presence of hydrogen or ammonium formate, further optionally deprotection of hydroxyl group with suitable acid/s or acid derivatives in organic solvents. The reaction may take place in an aqueous or non-aqueous medium.

The reaction is carried out with a suitable metal catalyst which includes, but is not limited to metal or non-metal catalyst such as iron, zinc, magnesium, palladium, platinum, triphenylphosphine, and the like. Preferably the reducing agent is palladium.

The reaction is carried out in presence of an organic solvent such as C1-C4-alcoholic solvent, for example, methanol, ethanol, isopropyl alcohol, n-butanol and the like.

The reaction is carried out at a temperature of about 0°C to about 150°C. Preferably the reaction is carried out at about 20°C to about 40°C. The reaction is carried out for a period of about 1 hour to about 5 hour. Preferably the reaction is carried out for about 4 hour to about 5 hour. In particular, the reaction will proceed for a period of about 2 to 3 hrs using metal catalyst /ammonium derivative as reducing agent in suitable solvents such as alcohols or chlorinating solvents. The hydrogenation reaction takes place in-situ by generation of hydrogen gas in presence of metal catalyst like palladium-on-active charcoal with ammonium derivatives like ammonium formate.

After completion of the reaction, the reaction mixture may be filtered, diluted with water, pH adjusted to 10 to 12 by using aqueous base, which will not affect any racemization or increase any impurity, and then extracted into ester solvent, which is then distilled completely to provide crude. Optionally, the crude may be converted into its pharmaceutically acceptable salt such as hydrochloride salt.

The step e) involves demethylation by using an acid, which includes, but is not limited to methane sulphonic acid and acetic acid in presence of DL-methionine.

The demethylation reaction may be conducted at a temperature of about 50 to about 100 ?C, preferably, at about 75 to 85 ?C.

After completion of the reaction, the reaction mixture may be filtered, combined with water, pH adjusted to 10 to 12 by using aqueous base and then extracted into ester solvent, which is then distilled completely to provide crude. Optionally, the crude may be converted into its pharmaceutically acceptable salt such as hydrochloride salt.

The purity of Tapentadol or its pharmaceutically acceptable salt of the present invention is greater than or equal to 99% determined by HPLC.

In another aspect, the present invention provides a process for the preparation of intermediate of Tapentadol, (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine, which comprises:
a) reaction of 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methypropan-1-one with Wittig reagent in the presence of ether to provide (RS)-3-(3-methoxyphenyl)-N,N, 2-trimethylpent-en-1-amine;
b) resolution of the compound of step a) with (-)-O,O- dibenzoyl-L-tartaric acid (DBTA) to provide (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine (-)-O,O- dibenzoyl-L-tartaric acid salt; and
c) reacting the salt of step b) with an amine to provide (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine.
The inventors of the present invention conducted experimentations for the preparation of key intermediate of Formula VIIa according to prior art processes and found that the prior art process provides racemization in the later stages and in the work-up, due to the various reasons such as use of strong base, and the like. Therefore, there is a need for an alternative process, which involves Wittig reaction, resolution followed by desaltification to provide higher yield and purity.

In another aspect, the present invention provides a process for preparation of intermediate of Tapentadol, (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan-1-amine or its salt, which comprises reduction of (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine with metal catalyst and ammonium formate to provide (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan-1-amine or its salt.

The metal catalyst includes and is not limited to palladium catalyst on carbon. The use of ammonium formate provides simple work-up conditions, safe reaction conditions and requires lesser time period as compared to hydrogen gas.

In another aspect, there is provided a pharmaceutical composition comprising Tapentadol or its pharmaceutically acceptable salt prepared according to processes disclosed in the present invention and one or more pharmaceutically acceptable excipients. The pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. The tapentadol or its salt may also be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.

The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, which can be selected from but not restricted to methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, polyvinylpyrrolidone (povidone), polyvinylalcohol, crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium alginate Croscarmellose Sodium, Carboxymethyl cellulose, sodium starch glycolate or a combination of both.

While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not act as limitations.

The application of the invention can be seen by the following non limiting examples:

Example 1: Preparation of (2R,3R)-3-(3-hydroxyphenyl)-N,N,2-trimethylpentan-1-amine [Tapentadol hydrochloride].

Step i:
1-(3-Methoxyphenyl)propan-1-one (230 g), dimethylamine hydrochloride (228 g), paraformaldehyde (78 g) was suspended in isopropyl alcohol (1150 ml) and then added 30 % of hydrochloric acid (20 ml) under stirring at below room temperature. The temperature of the reaction mass was raised at reflux temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was distilled completely under vacuum. Water (460 ml) was added to the reaction mass and stirred for 10 minutes. The aqueous layer was washed with toluene, cooled to 10-20ºC and adjusted the pH of the reaction mass to 10-12 with 20% sodium hydroxide solution. The product was extracted with dichloromethane (1000 ml) and the organic layer was washed with water, and distilled out completely under vacuum to obtain the oily mass. This was directly taken as such for the next stage.
Step ii:
Above oily mass and potassium t-butoxide (125 g) was suspended in diisopropyl ether (1000 ml) and added ethyl triphenyl phosphonium bromide under stirring at room temperature. The reaction mass was stirred for 3 hours at room temperature. After completion of the reaction, cooled to 0-5oC and maintained for 30 min. The reaction mass was filtered, washed with diisopropyl ether and distilled out completely under vacuum. Ammonium chloride solution was added to the residue and stirred for 30 minutes. The reaction mass was extracted with dichloromethane (800 ml) and adjusted the pH of the organic layer to less than 1.0 with conc. hydrochloric acid. The resulted aqueous layer was treated with aqueous ammonia till the pH reached to about 9 and then dichloromethane (1200 ml) was added. Distilled out the organic layer completely under vacuum and the resulting oily mass was dried and taken for the next stage.
Step iii:
Ethyl acetate (550 ml) and O,O'-dibenzoyl-(2R,3R)-tartaric acid (85 g) was added to the above oily mass at room temperature. The reaction mass was refluxed for 5 to 6 hours, cooled to 20-30°C and maintained for 3 hours. The solid was filtered, washed with ethyl acetate and dried at 30 to 50°C for 4 hours to obtain 83 gm of (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine O,O'-dibenzoyl-(2R,3R)-tartaric acid salt.
Step iv:
(R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine O,O'-dibenzoyl-(2R,3R)-tartaric acid salt (82 gm) was suspended in ethyl acetate (453 ml) and diethyl amine (32 g) was added to the suspended mass. The reaction mass was stirred at room temperature for 4 to 5 hours, filtered and washed with ethyl acetate (330 ml). The filtrate was distilled out completely under vacuum at 50oC and the resulting oily mass was dried and taken for the next stage.
Step v:
(R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (20 gm) of above oily mass was suspended in methanol (200 ml). Palladium carbon (50% wet 2 g) and acetic acid (51 g) were added to the suspended mass. Further, ammonium formate solution (54 gm of ammonium formate in 40 ml of water) was added slowly to the reaction mixture. The reaction mass was stirred at room temperature for 2-3 hours. After completion of the reaction, filtered the catalyst and washed with methanol (100 ml). The filtrate was distilled out completely under vacuum to obtain the residue. Water (80 ml) was added to the residue and stirred for 10 minutes. The pH of the reaction mass was adjusted to 10-12 with 10% sodium hydroxide solution. The product was extracted with ethyl acetate (200 ml) and the organic layer was washed with brine solution, distilled out completely under vacuum to obtain the residue. Acetone (100 ml) was added to the residue and purged the dry hydrogen chloride gas till the pH was about 2.0. The reaction mass was cooled to 0-5oC, maintained up to 2 hours, filtered and washed with acetone. The solid was dried under vacuum at 50oC to obtain (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine hydrochloride salt (90 g).
Step vi:
The mixture of methanesulphonic acid (450 ml), DL-methionine and (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine hydrochloride salt (90 g) was stirred at 75-85oC for 15 to 16 hours. After completion of the reaction, the reaction mass was cooled to 0-10oC, added to water and adjusted the pH of the reaction mass to 10-12 with 30% sodium hydroxide solution. The product was extracted with ethyl acetate (200 ml) and the organic layer was treated with ceca carbon, and washed with ethyl acetate. The resultant reaction mass was washed with water and distilled out completely under vacuum to obtain the residue. Acetone (360 ml) was added to the obtained residue, cooled to 10ºC and purged the dry hydrogen chloride gas till the pH was about 2.0 at 10oC. The reaction mass was maintained for 2 hours, filtered and washed with acetone (180 ml). The obtained crude product was purified with mixture of acetone (540 ml) and methanol (90 ml), dried under vacuum at 50oC to obtain the pure tapentadol hydrochloride (58 gm). Yield: 68.7 % with chiral HPLC purity > 99%.

Example 2: Preparation of 3-(dimethylamino-1-(3-methoxyphenyl)-2-methylpropan-1-one.
1-(3-Methoxyphenyl)propan-1-one (0.870kg), dimethylamine hydrochloride (0.862kg), paraformaldehyde (0.295 kg) was suspended in Ethyl alcohol (4.4 L) and then added 30 % of hydrochloric acid (0.760 L) under stirring at below room temperature. The temperature of the reaction mass was raised at reflux temperature and stirred for 12 hours. After completion of the reaction, the reaction mixture was distilled out completely under vacuum. Water (1.74L) was added to the reaction mass and stirred for 10 minutes. The aqueous layer was washed with toluene, cooled to 10-20oC and adjusted the pH of the reaction mass to 10-12 with 20% sodium hydroxide solution. The product was extracted with toluene (8.7 L) and the organic layer was washed with water, distilled out completely under vacuum to obtain the oily mass.

Example 3: Preparation of 3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine.
Oily mass (0.99 kg) obtained from Example-2 and potassium t-butoxide (1.26 kg) was suspended in tetrahydofuran (10 L) and ethyl triphenyl phosphonium bromide (3.35kg) was added under stirring at room temperature. The reaction mass was stirred for 3 hours at 60°-65°C. After completion of the reaction, cooled to 10-150C and maintained for 30 minutes. The reaction mass was filtered, washed with tetrahydofuran and distilled out completely under vacuum. Ammonium chloride solution was added to the residue and stirred for 30 minutes. The reaction mass was extracted with ethyl acetate (6.0 L) and adjusted the pH of the organic layer to less than 1.0 with conc. hydrochloric acid. The resulted aqueous layer was treated with aqueous ammonia till pH was about 9 and added the ethyl acetate (12 L). Distilled out the organic layer completely under vacuum and the resulting oily mass (0.8kg) was dried and taken for the next stage.

Example 4: Preparation of (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine O,O'-dibenzoyl-(2R,3R)-tartaric acid (DBTA) salt.
Diisopropyl ether (4.0 L) and O,O'-dibenzoyl-(2R,3R)-tartaric acid (1.3 kg) was added to the above oily mass (0.8 kg) obtained from example-3 at room temperature. The reaction mass was refluxed for 5 to 6 hours, cooled to 10-20°C and maintained for 1 hour. The solid was filtered and washed with diisopropyl ether (400 ml) and dried at 30 to 50°C for 4 hours to obtain (0.670 kg) of (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine O,O'-dibenzoyl-(2R,3R)-tartaric acid (DBTA) salt.

Example 5: Preparation of (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine.
(R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine O,O'-dibenzoyl-(2R,3R)-tartaric acid (DBTA) salt (0.670 kg) was suspended in diisopropyl ether (3.3 L) and diethyl amine (0.261 kg) was added to the suspended mass. The reaction mass was stirred at room temperature for 4 to 5 hours, filtered and washed with Diisopropyl ether (2.7 L). The filtrate was distilled out completely under vacuum at 50oC and the resulting oily mass was dried and taken for the next stage.

Example 6: Preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine.
(R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (300 gm) of above oily mass obtained from example-5 was suspended in ethyl alcohol (1200 ml), and palladium carbon (50% wet 30 g) and acetic acid (300 g) was added to the suspended mass. Further, slowly added ammonium formate solution (567 gm of ammonium formate in 1134 ml of water). The reaction mass was stirred at 40°-45°C for 2-3 hours. After completion of the reaction, filtered the catalyst and washed with Ethyl alcohol (300 ml). The filtrate was distilled out completely under vacuum to obtain the residue. Water (900 ml) was added to the resulting residue and stirred for 10 minutes. Adjusted the pH of the reaction mass to 10-12 with 10% sodium hydroxide solution. The product was extracted with ethyl acetate (1200 ml) and the organic layer was washed with brine solution, distilled out completely under vacuum to obtain the residue. Diisopropyl ether (1500 ml) was added to the obtained residue and dry hydrogen chloride gas was purged till the pH was about 2.0. The reaction mass was cooled to 0-50C, maintained up to 2 hours, filtered and washed with Diisopropyl ether. The solid was dried under vacuum at 50 0C to obtain (2R, 3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine hydrochloride salt (150 g).

Example 7: Preparation of tapentadol hydrochloride.
The mixture of methanesulphonic acid (450 ml), DL-methionine and (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine hydrochloride salt (150 g) was stirred at 90°-950C for 20 hours. After completion of the reaction, cooled to 0-10oC, added to water and adjusted the pH of the reaction mass to 10-12 with 30% sodium hydroxide solution. The product was extracted with dichloromethane (1500 ml) and then the organic layer was treated with ceca carbon, washed with dichloromethane. The resulting reaction mass was washed with water and distilled out completely under vacuum to obtain the residue. Acetone (750 ml) was added to the obtained residue and cooled to 20o C, the dry hydrogen chloride gas was purged till the pH was about 2.0 at 0 - 5° C. The reaction mass was maintained for 2 hours, filtered and washed with acetone (450 ml). The obtained crude product was purified with mixture of acetone (1200 ml) and ethyl alcohol (300 ml), dried under vacuum at 50o C to obtain the pure tapentadol hydrochloride (105 gm). Yield: 74.46 % with HPLC purity > 99%.

Example 8: Preparation of 1-[3-(benzyloxy)phenyl]-3-(dimethylamino)-2-methylpropan-1-one
1-[3-(Benzyloxy)phenyl]propan-1-one (200g), dimethylamine hydrochloride (135.8 g), paraformaldehyde (46.49 g) was suspended in isopropyl alcohol (2000 ml) and then added 30 % of hydrochloric acid (20 ml) under stirring at below room temperature. The temperature of the reaction mass was raised to reflux temperature and stirred for 13 hours. After completion of the reaction, the reaction mixture was distilled completely under vacuum. Water (400 ml) was added to the reaction mass and stirred for 15 minutes. The aqueous layer was washed with toluene, cooled to 10-20oC and adjusted the pH of the reaction mass to 10-12 with 20% sodium hydroxide solution. The product was extracted with dichloromethane (1000 ml) and the organic layer was washed with water, distilled out completely under vacuum to obtain the oily mass.

Example 9: Preparation of 3-[3-(benzyloxy)phenyl]-N,N,2-trimethylpent-3-en-1-amine
1-[3-(Benzyloxy)phenyl]-3-(dimethylamino)-2-methylpropan-1-one (200 g) of oily mass obtained in example 8 and potassium t-butoxide (75.41 g) was suspended in diisopropyl ether (2000 ml) and added ethyl triphenyl phosphonium bromide (518.5 g) under stirring at room temperature. The reaction mass was stirred for 4 hours at room temperature. After completion of the reaction, cooled to 0-5oC and maintained for 45 minutes. The reaction mass was filtered, washed with diisopropyl ether and distilled out completely under vacuum. Ammonium chloride solution was added to the residue and stirred for 45 minutes. The reaction was extracted with dichloromethane (800 ml) and then pH of the organic layer was adjusted to less than 1.0 with conc. hydrochloric acid. The resulted aqueous layer was treated with aqueous ammonia till pH was about 9 and added the dichloromethane (2000 ml). Distilled out the organic layer completely under vacuum and the resulting oily mass was dried and taken for the next stage.

Example 10: Preparation of (R)-3-[3-(benzyloxy)phenyl]-N,N,2-trimethylpent-3-en-1-amine O,O'-dibenzoyl-(2R,3R)-tartaric acid (DBTA) salt.
Ethyl acetate (600 ml) and O,O'-dibenzoyl-(2R,3R)-tartaric acid (146 g) was added to the 3-[3-(benzyloxy)phenyl]-N,N,2-trimethylpent-3-en-1-amine (120 gm) of oily mass (obtained in example 8) at room temperature. The reaction mass was refluxed for 4 to 5 hours, cooled to 15-25°C and maintained for 2.5 hours. The solid was filtered and washed with ethyl acetate (480 ml). The solid was dried at 45 to 50°C for 5 hours to obtain 102 gm of (R)- 3-[3-(benzyloxy)phenyl]-N,N,2-trimethylpent-3-en-1-amine O,O'-dibenzoyl-(2R,3R)-tartaric acid (DBTA) salt.

Example 11: Preparation of (R)-3-[3-(benzyloxy)phenyl]-N,N,2-trimethylpent-3-en-1-amine
(R)- 3-[3-(benzyloxy)phenyl]-N,N,2-trimethylpent-3-en-1-amine O,O'-dibenzoyl-(2R,3R)-tartaric acid (DBTA) salt (100 gm) was suspended in ethyl acetate (1000 ml). Diethyl amine (63.6 g) was added to the suspended mass. The reaction mass was stirred at room temperature for 3 to 5 hours, filtered and washed with ethyl acetate (300 ml). The filtrate was distilled out completely under vacuum at 45oC and the resulting oily mass was dried and taken for the next stage.

Example 12: Preparation of Tapentadol hydrochloride.
(R)-3-[3-(benzyloxy)phenyl]-N,N,2-trimethylpent-3-en-1-amine (30 gm) of oily mass (obtained in example 11) was suspended in methanol (300 ml). Palladium carbon (50% wet 3.0 g) and acetic acid (58 g) were added to the suspended mass. Further, ammonium formate solution (61 gm of ammonium formate in 122 ml of water) was added slowly. The reaction mass was stirred at room temperature for 2-3 hours. After completion of the reaction, filtered the catalyst and washed with methanol (60 ml), the filtrate was distilled out completely under vacuum to obtain the residue. Water (120 ml) was added to the resulting residue and stirred for 10 minutes. The pH of the reaction mass was adjusted to 10-12 with 10% sodium hydroxide solution. The product was extracted with ethyl acetate (300 ml) and then the organic layer was washed with brine solution, distilled out completely under vacuum to obtain the residue. Acetone (120 ml) was added to the residue and dry hydrogen chloride gas was purged till the pH was about 2.0. The reaction mass was cooled to 0-5oC, maintained up to 2 hour, filtered and washed with acetone. The solid was dried under vacuum at 50oC to obtain Tapentadol hydrochloride (6.4 gm). Yield: 30% with HPLC purity > 99%.
,CLAIMS:We claim:
1. A process for preparing a (2R, 3R)-compound of formula-(I),
(I)
or stereospecific isomers and/or pharmaceutically acceptable salts thereof, wherein R1 is a hydrogen atom or a hydroxyl-protecting group, independently selected from the group consisting of C1-C10 straight or branched chain alkyl, C2-C10 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or heterocycle, tri-C1-4 alkyl silyl, phenyl di C1-4 alkyl and diphenyl mono C1-4 alkyl silyl; wherein aryl or alkyl-aryl group is optionally substituted by a halogen atom; R2 and R3 are amino-protecting group, independently selected from the group consisting of hydrogen, C1-C10 straight or branched chain alkyl, C2-C10 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or heterocycle; wherein aryl or alkyl-aryl group is optionally substituted by a halogen atom, which comprises:
a) reaction of compound of formula IV with Wittig reagent to provide a compound of formula V;

b) resolution of the compound of formula V using resolving agent A to provide compound of formula VI;

c) reaction of the compound of formula VI with a base to provide compound of formula VII;

d) reduction of the compound of formula VII with metal catalyst to provide compound of formula I.
2. The process of claim 1, wherein the Wittig reagent is ethyltriphenylphosphonium halides.
3. The process of claim 1, wherein the resolving agent A is selected from one or more of (-)-O,O-dibenzyl-L-tartaric acidmonohydrate, D-(-)-tartaric acid, L-(+)-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (-)-dibenzoyl –L-tartaric acid, (+) – dibenzoyl – D-tartaric acid and hydrates thereof.
4. The process of claim 1, wherein the base in step c) is selected from one or more of ammonia, alkyl amine, metal alkoxides and metal carbonates.
5. The process of claim 1, wherein the metal catalyst is selected from one or more of palladium, iron, zinc, magnesium, platinum and triphenylphosphine.
6. An intermediate of formula (VI) or its salts:

wherein R1 is a hydrogen atom or a hydroxyl-protecting group, independently selected from the group consisting of C1-C10 straight or branched chain alkyl, C2-C10 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or heterocycle, tri-C1-4 alkyl silyl, phenyl di C1-4 alkyl and diphenyl mono C1-4 alkyl silyl; wherein aryl or alkyl-aryl group is optionally substituted by a halogen atom; R2 and R3 are amino-protecting group, independently selected from the group consisting of hydrogen, C1-C10 straight or branched chain alkyl, C2-C10 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or heterocycle; wherein aryl or alkyl-aryl group is optionally substituted by a halogen atom; and A is optically active acid selected from one or more of (-)-O,O-dibenzyl-L-tartaric acidmonohydrate, D-(-)-tartaric acid, L-(+)-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (-)-dibenzoyl –L-tartaric acid, (+) – dibenzoyl – D-tartaric acid and hydrates thereof.
7. The compound of claim 6, which is (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine (-)-O,O- dibenzoyl-L-tartaric acid salt.
8. A process for preparation of novel intermediate of formula (VI) or its salts:

wherein the method comprises:
a) reaction of compound of formula IV with Wittig reagent to provide a compound of formula V;

b) resolution of the compound of formula V using resolving agent A to provide compound of formula VI;
,
wherein, R1, R2, R3 and A are as defined in claim 6.
9. A process for preparation of intermediate of Tapentadol, 2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan-1-amine or its salt, which comprises reduction of (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-1-amine with metal catalyst and ammonium formate to provide (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan-1-amine or its salt.
10. The process of claim 9, wherein the compound of (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan-1-amine or its salt is further converted to Tapentadol or its salts.