Field of the Invention:

The present invention relates to a novel process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol represented by the structural formula-1 and its hydrochloride salt represented by structural formula-la. The present invention also provides novel intermediates which are useful in the preparation of 3-[(17?,2i?)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1.

3-[( lR,2R)-3-(dimethylamino)-1 -ethyl-2-methylpropyl]phenol hydrochloride is developed by Grunenthal in conjunction with Johnson & Johnson Pharmaceutical Reasearch and development and is marketed under the trade names Nucynta, Palexia, Zyntap. "3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol" is commonly known as Tapentadol. It is a centrally acting analgesic with dual mode of action as an agonist of n-opioid receptor and norepinephrine reuptake inhibitor.

Background of the invention:

3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride and its process for the preparation was first disclosed in US RE39593. The disclosed process involves the reaction of 3-bromoanisole with l-dimethylamino-2-methylpentane-3-one to form diastereomeric mixture of l-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. The separation of the diastereomeric isomers, i.e., the two enantiomeric pairs is carried out by precipitating as hydrochloride salt with trimethylchloro silane/water in 2-butanone. The resolution of the racemic mixture of the two enantiomers of (2S,3S) and (2R,3R) isomers are carried out by separation on a chiral HPLC column to provide (2S,3S)-l-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. The resolved intermediate is then converted into its corresponding chloro compound, followed by reduction with Zinc borohydride and finally demethylated using HBr.

The main drawback of the above said process is the usage of trimethyl chlorosilane in the diastereomeric separation, which is hazardous and highly flammable, hence not advisable to use in the industrial scale. The other drawback of this process is resolution of enantiomers by chiral HPLC, which is cost-effective, not amenable for commercial synthesis on industrial scale and thereby making the process commercially unfeasible. The usage of reducing agents in the above process, such as zinc borohydride which is hazardous substance and poses considerable fire when used on the large-scale, hence it is not advisable to use on large scale.

PCT publications WO 2008012283, WO2008012047 and WO 2008012046 are disclosed a process for the preparation of (2S,3R)-l-(dimethylamino)-3-(3-methoxy phenyl)-2-methylpentan-3-ol, which is a key intermediate in the synthesis of 3-[(\R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride. The disclosed process involves the reaction of l-(3-methoxyphenyl)propan-l-one, dimethylamine and formaldehyde provides 3-(dimethylamino)-l-(3-methoxyphenyl)-2-methylpropan-l-one, which on resolution by treating with L-(-)-DBTA provides the (2S)-3-(dimethylamino)-l-(3-methoxyphenyl)-2-methylpropan-l-one and the obtained compound is further treated with ethyl magnesium halide.

U.S. Patent US7649114 disclosed a resolution method for the separation of the two enantiomers from the enantiomeric pair, (2R,3R)/(2S,3S)-l-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, with the aid of a chiral acid, such as (+)-di-0,0'-p-toluoyltartaric acid, (-)-di-0,0'-p-toluoyltartaric acid and D-(-)-tartaric acid, in the presence of a suitable solvent such as 2-butanone.

PCT publication WO2011107876 disclosed a resolution method for the separation of the two enantiomers from the enantiomeric pair, (2S,3R)/(2R,3S)-l-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol, with the aid of chiral auxiliary, such as (S)-naproxen. The said publication also disclosed a resolution method for the separation of enantiomers from the enantiomeric pair, (2R,3R)/(2S,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine using an optically active acid, such as di-p-toluoyl-L-tartaric acid and di-benzoyl-L-tartaric acid.

The main drawback of the above mentioned methods for the preparation of 3-[(li?,2i?)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride is that all the processes are leading to the enantiomeric separation of its intermediates, which increases the total number of steps of the reaction resulting the usage of additional solvents and reagents making the process expensive.

Therefore, there is an obvious need for the development of a cost-effective and industrially viable process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyljphenol hydrochloride and that do not involve the chiral chromatographic technique.

Brief description of the invention:

The first aspect of the present invention is to provide novel intermediate compounds which are useful in the synthesis of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl] phenol compound of formula-1 as well as its hydrochloride salt compound of formula-la.

The second aspect of the present invention is to provide a novel process for the preparation of (2S)-1 -(3-methoxyphenyl)-2-methyl-3-(N-substituted-N-( 1 -phenylethyl)amino) propan-1-one compound of general formula-4, comprising of reacting the l-(3-methoxyphenyl)propan-l-one compound of formula-2 with 1-phenylethylamine derivative compound of general formula-3 with formaldehyde in presence of an acid in a suitable solvent, followed by hydrolysis provides compound of general formula-4.

The third aspect of the present invention is to provide a process for preparation of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-1 -(N-substituted-N-( 1 -phenylethyl)amino)pentan-3-ol compound of general formula-5, comprising of reacting the (2S)-l-(3-methoxyphenyl)-2-methyl-3-(N-substituted-N-(l-phenylethyl)amino)propan-l-one compound of general formula-4 with ethyl magnesium halide in a suitable solvent to provide compound of general formula-5.

The fourth aspect of the present invention is to provide a process for preparation of (3R,4S)-3 -(3 -methoxyphenyl)-4-methyl-5-(N-substituted-N-( 1 -phenylethyl)amino)pent-1 -en-3-ol compound of general formula-10, comprising of reacting the (2S)-l-(3-methoxyphenyl)-2-methyl-3-(N-substituted-N-(l-phenylethyl)amino)propan-l-one compound of general formula-4 with vinyl magnesium halide in a suitable solvent to provide compound of general formula-10.

The fifth aspect of the present invention is to provide a process for the preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-8, comprising of N-methylating (2R,3R)-3-(3-methoxyphenyl)-2-methyl-N-substituted-pentan-l-amine compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide compound of formula-8.

The sixth aspect of the present invention is to provide a novel process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of acylation of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-(N-substimted-N-(l-phenylethyl)amino)pentan-3-ol compound of general formula-5, followed by catalytic hydrogenation, N-methylation and O-demethylation to provide compound of formula-1.

The seventh aspect of the present invention is to provide alternative process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of dehydration of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-(N-substituted-N-(l-phenylethyl) amino)pentan-3-ol compound of general formula-5, followed by catalytic hydrogenation, N-methylation and O-demethylation provides compound of formula-1.

The eighth aspect of the present invention is to provide another process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of acylation of (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N-(l-phenylethyl) amino)pent-l-en-3-ol compound of general formula-10, followed by catalytic hydrogenation, N-methylation and O-demethylation provides compound of formula-1.

The ninth aspect of the present invention is to provide another process for the preparation of 3-[(l/?,2i?)-3-(dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula-1, comprising of catalytic hydrogenation of (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N-(l-phenylethyl)amino)pent-l-en-3-ol compound of general formula-10, followed by dehydration, catalytic hydrogenation, N-methylation and O-demethylation provides compound of formula-1.

The tenth aspect of the present invention is to provide another process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula-1, comprising of catalytic hydrogenation of (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N-(l-phenylethyl)amino)pent-l-en-3-ol compound of general formula-10, followed by acylation, catalytic hydrogenation, N-methylation and O-demethylation provides compound of formula-1.

The eleventh aspect of the present invention is to provide a process for the preparation of crystalline form-B of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride compound of formula-la.

The twelfth aspect of the present invention is to provide (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol, which is an useful intermediate in the synthesis of -[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1 and its hydrochloride salt compound of formula-la, and process for its preparation.

The thirteenth aspect of the present invention is to provide a process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of catalytic hydrogenation of (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15, followed by dehydration, reduction and O-demethylation provides compound of formula-1.
The fourteenth aspect of the present invention is to provide alternative process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of acylation of compound of formula-15, followed by catalytic hydrogenation, and O-demethylation provides compound of formula-1.

Advantages of the present invention:

• Produces 3-[(lR,2R)-3-(dimethylamino)-1 -ethyl-2-methylpropyl]phenol in shorter reaction time.
• Avoids chiral chromatographic separation techniques.

• Avoids the additional resolution step using chiral reagents, which inturn avoids the usage of additional reagents and solvents.

• Avoids trimethylchlorosilane in the diastereomeric separation, which is highly flammable liquid and hazardous.

• Avoids the usage of zinc borohydride which is hazardous and poses considerable fire.

• Provides commercially viable and cost-effecetive and environmental friendly process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol.

Detailed description of the invention:

The "suitable solvent" used in the present invention is selected from, but are not limited to "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert.butyl acetate and the like; "ether solvents" such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, 1,2-dimethoxy ethane diisopropyl ethyl and the like; "hydrocarbon solvents" such as toluene, hexane, heptane, xylene, benzene, pet.ether, cyclohexane and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethyl sulfoxide, acetonitrile and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; and "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butanol and the like; "chloro solvents" such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; polar solvents such as water; and also mixtures thereof.

As used herein the "base" is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate; sodium bicarbonate and potassium bicarbonate; and ammonia; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, piperidine, pyridine, tributyl amine, 4-dimethylaminopyridine, N-methyl morpholine and the like.

The "suitable acylating agent" used in the present invention is selected from, but are not limited to anhydrides and halides of acetic acid, phenyl acetic acid, chloro acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, benzoic acid, chlorobenzoic acid, terephthalic acid, phthalic acid, succinic acid, mono C1-C4 alkyl esters of succinic acid, oxalic acid, mono C1-C4 alkyl esters of oxalic acid such as ethyl oxalyl chloride and methyl oxalyl chloride, and mixed anhydride of formic acid such as ethylchloroformate, methylchloroformate and acetylsalicyloyl chloride.

The "suitable metal catalyst" used for hydrogenation in the present invention is selected from, but are not limited to Pd, Pt, Ru, Rh catalysts such as Pd, Pd-C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3 [tris(dibenzylidene acetone)dipalladium], palladium thiomethyl phenylglutaramide, palladium on metal oxide, palladium on zeolites, Pt, Pt-C, Pt02, Ru-C, Rh-C, rhodium on alumina; and Raney-Ni.

The "suitable methylating agent" herein the present invention refers, but not limited to dimethyl sulfate, methyl iodide, dimethyl carbonate, methyl methane sulfonate, methyl triflate, trimethyl oxonium tetrafluoroborate, N-methyl methane sulfonamide, formaldehyde/formic acid and formaldehyde/sodium borohydride.

The "suitable demethylaying agent" herein the present invention is selected from, but are not limited to hydrobromic acid with or without carboxylic acid such as formic acid, acetic acid; methane sulfonic acid, methionine, diisobutyl aluminium hydride, pyridine chloride, lewis acids like aluminium chloride, boron tribromide and mixtures thereof.

The "suitable dehydrating agent" used in the present invention is selected from, but are not limited to inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like; and organic acid such as formic acid and methane sulfonic acid; acid anhydrides such as trifluoroacetic anhydride and acetic anhydride; phosphorous pentoxide; phosphoryl chloride; phosphoric acid; and dicyclohexylcarbodiimide.

As used herein, the term "C1-C4 alkyl" refers to alkyl group having 1 to 4 carbon atoms. Examples of Ci_ C4 alkyl groups include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and t-butyl.

As used herein the term "C6-C10 aryl" refers to aromatic ring having 6 to 10 carbon atoms. Examples of C6-C10 aryl groups includes, without limitation phenyl, naphthyl and pyridine.

As used herein, the term "cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring. A "C3-C7 cycloalkyl" refers to cycloalkyl group having 3 to 7 carbon atoms. Examples of monocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The first aspect of the present invention is to provide novel compounds represented by following structural formulae:

Wherein, "acyl" represents CH3-CO-, CF3-CO-, CH2C1-C0-, CHC12-C0-, CCI3-CO-, CH3O-CO-, CH3CH2O-CO-, CH30-CO-CO, CH3CH2O-CO-CO-, phenyl-CO-, or meta-CH3COO-phenyl-CO- , Cl-phenyl-CO-, HOOC-CH2-CH2-CO-, (C1-C4alkyl)-OOC-CH2-CH2-CO, ortho-HOOC-Phenyl-CO, ortho-(Ci-C4alkyl)-phenyl-CO-, para-HOOC-Phenyl-CO, para-(d-C4alkyl)-phenyl-CO- and the like;
"R" represents -H, -CH3, -CH2Ph in which Ph is optionally substituted with C1-C4 alkyl, halogen, C6-C10 aryl, C3-C7 cycloalkyl, -OH, -O-C1-C4 alkyl and the like; and "Ri" represents -H;
which are useful intermediates in the synthesis of 3-[(l/?,2i?)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1 as well as its hydrochloride salt compound of formula-la.
The second aspect of the present invention is to provide a novel process for the preparation of (2S)-1 -(3-methoxyphenyl)-2-methyl-3-(N-substituted-N-( 1 -phenylethyl)amino) propan-1-one compound of general formula-4, comprising of reacting the l-(3-methoxyphenyl) propan-1-one compound of formula-2 with 1-phenylethylamine derivative compound of general formula-3 with formaldehyde in presence of an acid in a suitable solvent, followed by hydrolysis provides compound of general formula-4.
Wherein, the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar aprotic solvents, hydrocarbon solvents and alcoholic solvents; and the "acid" refers to inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid.

The third aspect of the present invention is to provide a process for preparation of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-(N-substituted-N-(l-phenylethyl)amino)pentan-3-ol compound of general formula-5, comprising of reacting (2S)-l-(3-methoxyphenyi)-2-methyl-3-(N-substituted-N-(l-phenylethyl)amino)propan-l-one compound of general formula-4 with ethyl magnesium halide in a suitable solvent to provide compound of general formula-5.

Wherein, the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and hydrocarbon solvents; and the "ethyl magnesium halide" used is selected from ethyl magnesium bromide and ethyl magnesium chloride.

The fourth aspect of the present invention is to provide a process for the preparation of (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N-(l-phenylethyl)amino)pent-l-en-3-ol compound of general formula-10, comprising of reacting (2S)-l-(3-methoxyphenyl)-2-methyl-3-(N-substituted-N-(l-phenylethyl)amino)propan-l-one compound of general formula-4 with vinyl magnesium halide in a suitable solvent to provide compound of general formula-10.

Wherein, the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and hydrocarbon solvents; and the "vinyl magnesium halide" used is selected from vinyl magnesium bromide and vinyl magnesium chloride.

The fifth aspect of the present invention is to provide a process for the preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-8, comprising of N-methylating the (2R,3R)-3-(3-methoxyphenyl)-2-methyl-N-substituted-pentan-1-amine compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent provides compound of formula-8.

Wherein, the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof; and the "suitable methylating agent" is selected from dimethylsulfate, methyl iodide, dimethylcarbonate, methyl methane sulfonate, methyl triflate, trimethyl oxonium tetrafluoroborate, N-methyl methane sulfonamide, formaldehyde/formic acid and formaldehyde/sodium borohydride.

The sixth aspect of the present invention is to provide a novel process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of the following steps:

a) Acylating the (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-(N-substituted-N-(l-phenyl ethyl)amino)pentan-3-ol compound of general formula-5 with a suitable acylating agent in presence or absence of a base in a suitable solvent to provide its corresponding acyl derivative compound of general formula-6,

b) hydrogenating the compound of general formula-6 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2R,3R)-3-(3-methoxyphenyl)-2-methyl-N-substituted-pentan-1-amine compound of general formula-7,

c) N-methylating the compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-8,

d) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl] phenol compound of formula-1.

Wherein,

In step-a) the "suitable acylating agent" is selected from anhydrides and halides of acetic acid, phenyl acetic acid, chloro acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, benzoic acid, chlorobenzoic acid, terephthalic acid, phthalic acid, succinic acid, mono C1-C4 alkyl esters of succinic acid, oxalic acid, mono C1-C4 alkyl esters of oxalic acid such as ethyl oxalyl chloride and methyl oxalyl chloride, and mixed anhydride of formic acid such as ethylchloroformate, methylchloroformate and acetylsalicyloyl chloride; and the "base" is inorganic or organic base; In step-b) the "suitable metal catalyst" is selected from Pd, Pt, Ru and Rh catalysts such as Pd, Pd-C, Pd(OH)2, Pd(OAc)2, PdCl2, Pt, PtO2, Ru-C and Rh-C; and Raney-Ni;

In step-c) the "suitable methylating agent" and "suitable solvent" are same as defined in fifth aspect of the present invention;

In step-d) the "suitable demethylating agent" is selected from hydrobromic acid optionally in combination with carboxylic acid such as formic acid, acetic acid; methane sulfonic acid, methionine, diisobutyl aluminium hydride, pyridine chloride, lewis acids like aluminium chloride, boron tribromide and mixtures thereof;

the "suitable solvent" used in step-(a) and step-(b) is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably alcoholic solvents and ether solvents; and

the "suitable solvent" used in step-(d) is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, polar solvents, chloro solvents and/or mixtures thereof, preferably polar solvents and chloro solvents.

The seventh aspect of the present invention is to provide an alternative process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl] phenol compound of formula-1, comprising of the following steps:

a) Dehydrating the (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-(N-substiruted-N-(l-phenyl ethyl)amino)pentan-3-ol compound of general formula-5 with a suitable dehydrating agent in a suitable solvent to provide (2R)-3-(3-methoxyphenyl)-2-methyl-N-substituted-N-( 1 -phenyl ethyl)pent-3 -en-1 -amine compound of general formula-9,

b) hydrogenating the compound of general formula-9 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2R,3R)-3-(3-methoxyphenyl)-2-methyl-N-substituted-pentan-1-amine compound of general formula-7,

c) N-methylating the compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-8,

d) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide 3-[(l/?,2/?)-3-(dimethylamino)-l-ethyl-2-methyl propyl] phenol compound of formula-1.

Wherein,

In step-a) the "suitable dehydrating agent" is selected from inorganic acids, organic acids, acid anhydrides, phosphorous pentoxide; phosphoryl chloride; phosphoric acid; dicyclohexyl carbodiimide; and the "suitable solvent" used is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents; and

the "suitable metal catalyst", "suitable methylating agent", "suitable demethylating agent" and "suitable solvents" used in step-(b), step-(c) & step-(d) are same as defined in step-(b), step-(c) & step-(d) of sixth aspect of the present invention respectively;

The eighth aspect of the present invention is to provide another process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyljphenol compound of formula-1, comprising of the following steps:

a) Acylating the (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N-(l-phenyl ethyl)amino)pent-l-en-3-ol compound of general formula-10 with a suitable acylating agent in presence or absence of a base in a suitable solvent to provide its corresponding acylated derivative compound of general formula-11,

b) hydrogenating the compound of general formula-11 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2R,3R)-3-(3-methoxyphenyl)-2-methyl-N-substituted-pentan-l-amine compound of general formula-7, c) N-methylating the compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-8,

d) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula-1.

Wherein, the "suitable acylating agent", "base" "suitable metal catalyst", "suitable methylating agent", "suitable demethylating agent" and "suitable solvents" used in step-(a), step-(b), step-(c) & step-(d) are same as defined in step-(a), step-(b), step-(c) & step-(d) of sixth aspect of the present invention respectively;

The ninth aspect of the present invention is to provide another process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula-1, comprising of the following steps:
a) Hydrogenating the (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N-(lR-phenyl ethyl)amino)pent-l-en-3-ol compound of general formula-10 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-(N-substituted-amino)pentan-3-ol compound of general formula-12,

b) dehydrating the compound of general formula-12 with a suitable dehydrating agent in a suitable solvent to provide (2R)-3-(3-methoxyphenyl)-2-methyl-N-substituted-pent-3-en-1-amine derivatives compound of general formula-14,

c) hydrogenating the compound of general formula-14 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2R,3R)-3-(3-methoxyphenyl)-2-methyl-N-substituted-pentan-l-amine compound of general formula- 7,

d) N-methylating the compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-8,

e) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl] phenol compound of formula-1.

Wherein, the "suitable metal catalyst", "suitable methylating agent", "suitable demethylating agent" and "suitable solvents" used in step-(a), step-(c), step-(d) & step-(e) are same as defined in step-(b), step-(c) & step-(d) of sixth aspect of the present invention respectively;

The "suitable dehydrating agent" and "suitable solvent" used in step-(b) are same as defined in step-(a) of seventh aspect of the present invention.

In an alternative process, the (2R)-3-(3-methoxyphenyl)-2-methyl-N-substituted-pent-3-en-1-amine compound of general formula-14 in the above aspect undergoes methylation,

followed by catalytic hydrogenation and then demethylation to provide 3-[(\R,2R)-3-(dimethylamino)-1 -ethyl-2-methylpropyl]phenol compound of formula-1.

The tenth aspect of the present invention is to provide another process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula-1, comprising of the following steps:

a) Hydrogenating the (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N-(l-phenyl ethyl)amino)pent-l-en-3-ol compound of general formula-10 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-(N-substituted-amino)pentan-3-ol compound of general formula-12,

b) acylating the compound of general formula-12 with a suitable acylating agent in presence or absence of a base in a suitable solvent to provide its corresponding acylated derivative compound of general formula-13,

c) hydrogenating the compound of general formula-13 with a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2R,3R)-3-(3-methoxy phenyl)-2-methyl-N-substituted-pentan-1-amine compound of general formula-7,

d) N-methylating the compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-8,

e) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl] phenol compound of formula-1.

Wherein, the "suitable metal catalyst", "suitable acylating agent", "base", "suitable methylating agent", "suitable demethylating agent" and "suitable solvents" used in step-(a), step-(b), step-(c), step-(d) & step-(e) are same as defined in step-(a), step-(b), step-(c) & step-(d) of sixth aspect of the present invention respectively;

In an alternative process, the compound of general formula-13 in the above aspect undergoes methylation, followed by catalytic reduction and then demethylation to provide 3-[(1R,2R)-3-(dimethylamino)-1 -ethyl-2-methylpropyl]phenol compound of formula-1.

In an alternative process, the compounds of general formula-13 and 14 of the present invention undergo methylation and demethylation, followed by catalytic reduction provides the 3-[( lR,2R)-3-(dimethylamino)-1 -ethyl-2-methylpropyl]phenol compound of formula-1.

The eleventh aspect of the present invention is to provide a process for the preparation of crystalline form-B of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride compound of formula-la, comprising of:

a) Dissolving the 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1 in ethyl acetate,

b) filtering the reaction mixture,

c) adjusting pH of filtrate to 1-2 with ethyl acetate-HCl,

d) stirring the reaction mixture,

e) filtering the precipitated solid and washing with ester solvent,

f) drying the solid to get crystalline form-B of compound of formula-1 a.

The compound of general formula-14 is commercially available and can be prepared by the known methods.

In the present invention, the compounds of general formula-5, 10, 12 and compound of formula-15 undergo tosylation or mesylation to provide its corresponding tosylated or mesylated derivatives. The obtained compound further hydrogenated in presence of suitable metal catalyst under hydrogen pressure to provide (2R,3R)-3-(3-methoxyphenyl)-2-methyl-N-substituted-pentan-1-amine compound of general formula-7.

The starting materials used in the present invention are commercially available and also can be prepared by any of the known methods.

All the intermediate compounds of the present invention are converted into their acid addition salts like hydrochloride, hydrobromide and hydrogen sulfate salts.

The twelfth aspect of the present invention is to provide (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15 represented by the following structural formula:

Formula-15 which is an useful intermediate in the synthesis of Tapentadol.

The twelfth aspect of the present invention is to provide a process for the preparation of (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15, comprising of reacting the (S)-3-(dimethylamino)-l-(3-methoxyphenyl)-2-methylpropan-l-one compound of formula-14 with vinyl magnesium halide in a suitable solvent to provide compound of formula-15.

Wherein, the "vinyl magnesium halide" is selected from vinyl magnesium chloride and vinyl magnesium bromide; and the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and hydrocarbon solvents.

The "vinyl magnesium halide" employed is in molar proportions ranging from 0.8 to 2.5 molar equivalents per one mole of compound of formula-14.

The thirteenth aspect of the present invention provides a process for preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of:

a) Hydrogenating the (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15 in presence of a suitable metal catalyst and hydrogen gas in a suitable solvent to provide (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-ol compound of formula-16,

b) dehydrating the compound of formula-16 in-situ by treating it with a suitable dehydrating agent in a suitable solvent to provide (R,Z)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine compound of formula-17,

c) reducing the compound of formula-17 in-situ with a suitable reducing agent in a suitable solvent to provide (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-8,

d) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide compound of formula-1. Wherein, In step-a) the "suitable metal catalyst" is selected from Pd, Pt, Ru and Rh catalysts such as Pd, Pd-C, Pd(OH)2, Pd(OAc)2, PdCl2, Pt, Pt02, Pt-C, Ru-C and Rh-C; and Raney-Ni; and the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and alcoholic solvents;

In step-b) the "suitable dehydrating agent" is selected from inorganic acids, organic acids, acid anhydrides, phosphorous pentoxide; phosphoryl chloride; phosphoric acid; and dicyclohexyl carbodiimide; and the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents;

In step-c) the "suitable reducing agent" is selected from Ru, Rh metal catalysts such as Ru-C and Rh-C in presence of hydrogen; Raney-Ni in presence of hydrogen; sodium borohydride; and Pd, Pt, Ru, Rh and Re catalysts such as Pd, Pd-C, Pd(OH)2, PdCl2, Pd(OAC)2, Pt, Pt-C, PtO2, Ru-C, Rh-C, ReIO2(PPh3)2, ReOCl3(PPh3)2, ReOCl3(dppm), and Re2O7 in presence of hydrogen source such as silane and sodium borohydride; the "silane" is selected from dimethylphenyl silane, phenyl silane, triethyl silane, triphenyl silane and poly methylhydrosiloxane; and the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof; preferably hydrocarbon solvents, alcoholic solvents, chloro solvents and polar aprotic solvents; and

In step-d) the "suitable demethylating agent" is selected from hydrobromic acid optionally in combination with carboxylic acid such as formic acid, acetic acid; methane sulfonic acid, methionine, diisobutyl aluminium hydride, pyridine chloride, lewis acid such as aluminium chloride boron tribromide and mixtures thereof; and the "suitable solvent" is selected from is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents and chloro solvents, preferably polar solvents and chloro solvents.

The fourteenth aspect of the present invention provides a process for preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of:

a) Acylating the (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15 with a suitable acylating agent in presence or absence of a base in a suitable solvent to provide its corresponding acyl derivative compound of general formula-18,

b) hydrogenating the compound of general formula-18 in-situ in presence of a suitable metal catalyst and hydrogen gas in a suitable solvent to provide (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethyl pentan-1 -amine compound of formula-8,

c) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide compound of formula-1.

Wherein,

In step-a) the "suitable acylating agent" is selected from anhydrides and halides of acetic acid, phenyl acetic acid, chloro acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, benzoic acid, chlorobenzoic acid, terephthalic acid, phthalic acid, succinic acid, mono C1-C4 alkyl esters of succinic acid, oxalic acid, mono C1-C4 alkyl esters of oxalic acid such as ethyl oxalyl chloride and methyl oxalyl chloride, and mixed anhydride of formic acid such as ethyl chloroformate, methyl chloroformate and acetyl salicyloyl chloride; the "base" is inorganic or organic base; and the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and alcoholic solvents; and the "suitable metal catalyst", "suitable demethylating agent" and "suitable solvents used in step-(b) and step-(c) are same as defined in step-(a) and step-(d) of thirteenth aspect of the present invention respectively.

3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1 obtained by the present invention is further converted into its hydrochloride salt compound of formula-la by treating it with a suitable HC1 source such as HC1, aq.HCl, ethyl acetate-HCl, isopropanol-HCl, diethyl ether-HCl and diisopropyl ether-HCl.

3-[(lR,2R)-3-(dimethylamino)-l -ethyl-2-methylpropyl]phenol hydrochloride compound of formula-la of the present invention can be further micronized or milled to get the desire particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

The present invention is schematically represented by the following schemes: Scheme-I: Wherein, R is selected from -H, -CH3, -CH2Ph in which Ph is optionally substituted with C1-C4 alkyl, halogen, C6-C10aryi, C3-C7 cycloalkyl,-OH,-O-C1-C4 alkyl.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention:

Examples:

Example-1: Preparation of crystalline form-B of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride (Formula-la) 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol (19 gms) was dissolved in ethyl acetate (80 ml) and the reaction mixture was filtered on hyflow bed. The PH of the obtained filtrate was adjusted to 1.5 using ethyl acetate-HCl at 25-35°C and the reaction mixture was stirred for 4 hours at 25-35°C. Filtered the precipitated solid and washed with ethyl acetate. Dried the obtained solid to get title compound. Yield: 19 gms.

Example-2: Preparation of (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol (Formula-15)

A solution of (S)-3-(dimethylamino)-l-(3-methoxyphenyl)-2-methylpropan-l-one compound of formula-14 (50 gms) in tetrahydrofuran (200 ml) was added slowly to vinyl magnesium bromide (88 gms) at 0-5°C under nitrogen atmosphere. The temperature of the reaction mixture was raised to 25-30°C and stirred for 3 hours. After completion of reaction, the reaction mixture was quenched with 15% ammonium chloride solution at 0-5°C. The temperature of the reaction mixture was raised to 20-30°C and stirred for 15 minutes. Both the organic and aqueous layers were separated; the aqueous layer was extracted with tetrahydrofuran. Both the organic layers were combined and dried with sodium sulfate and then distilled under reduced pressure to provide title compound. Yield: 40 gms.

Example-3: Preparation of (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-ol (Fomrula-16) (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol (5 gms) compound of formula-15 was dissolved in 13 ml ethanol. A suspension of palladium on active charcoal (0.35 gms) in ethanol (3 ml) was added to the reaction mixture under nitrogen atmosphere. Hydrogen gas with pressure of 5 bar was passed into the reaction mixture.

After completion of the reaction, the reaction mixture was filtered and the filtrate was distilled completely to get title compound. Yield: 3.4 gms.

Example-4: Preparation of (R,Z)-3-(3-methoxyphenyl)-N,N,2-trimethyIpent-3-en-l-amine (Formula-17) 36 wt. % aqueous hydrochloric acid (5.25 ml) was added slowly to (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-ol (3 gms) compound of formula-16 obtained in example-3. The reaction mixture was heated slowly to 50°C and stirred for 6 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to room temperature and water was added to it. The reaction mixture was basified with 32 wt% sodium hydroxide at an internal temperature of 20°C. Ethyl acetate was added to the reaction mixture; both the organic and aqueous layers were separated, the organic layer was distilled off completely under reduced pressure to get title compound. Yield: 2.5 gms.

Example-5: Preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine (Formula-8) A solution of sodium borohydride (0.65 gms) in ethanol (5 ml) was added slowly to a mixture of (R,Z)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-l-amine compound of formula-17 (2 gms) obtained in example-4 and 10 ml of ethanol at room temperature and stirred for 3 hours at room temperature. After completion of the reaction, water was added to the reaction mixture. Reaction mixture was extracted with ethyl acetate. Both the organic and aqueous layers were separated; the solvent from the organic layer was distilled off completely to get title compound. Yield: 1.32 gms.

Exampel-6: Preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyI]phenol (Formula-1) (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-8 (4.9 gms) was dissolved in methane sulfonic acid (25 ml). Methionine (4.7 gms) was added to the obtained solution and the reaction mixture was stirred for 20 hours at 75-80°C. After completion of the reaction, the reaction mixture was cooled to 15-25°C and water was added to it. The reaction mixture was basified with 28% sodium hydroxide at a temperature below 50°C.

Ethyl acetate was added to the reaction mixture and stirred for 30 minutes. Both the organic and aqueous layers were separated; the organic layer was filtered over the silica gel and washed with ethyl acetate. The solvent from the obtained filtrate was distilled off completely under reduced pressure to get title compound. Yield: 5.5 gms.

Example-7: Preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethyIpentan-l-amine (Formula-8) (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15 (15 gms) was dissolved in 2-methyl tetrahydrofuran (90 ml) and trifluoroacetic anhydride (18.9 gms) was added it. The reaction mixture was heated to 40-45°C and stirred for 4 hours under stirring. After completion of the reaction, the reaction mixture containing (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-yl 2,2,2-trifluoroacetate compound of formula-18a (where "acyl"=CF3-CO-) was cooled to room temperature and Pd-C (2 gms) was added to the reaction mixture under nitrogen atmosphere. The reaction mixture was transferred into autoclave and applied hydrogen gas with pressure of 3 bar to the reaction mixture over a period of 16 hours. Filtered the catalyst through hyflow bed, water was added to the filtrate and extracted with dichloromethane. Both the organic and aqueous layers were separated; the solvent from organic layer was distilled off completely to get title compound. Yield: 13 gms.

We claim:

1. (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15 represented by the following structure.

2. A process for preparation of (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15, comprising of reacting the (S)-3-(dimethylamino)-1 -(3-methoxyphenyl)-2-methylpropan-1 -one compound of formula-14 Formula-14 with vinyl magnesium halide in a suitable solvent to provide compound of formula-15.

3. The process according to claim-2, wherein:

the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and hydrocarbon solvents; and the vinyl magnesium halide is selected from vinyl magnesium chloride and vinyl magnesium bromide.

4. The process according to claim 1, wherein the vinyl magnesium halide employed is in molar proportions ranging from 0.8 to 2.5 molar equivalents per one mole of compound of formula-14.

5. The process according to claim-2 to 4, for the preparation of (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15, comprising of reacting the (S)-3-(dimethylamino)-1 -(3 -methoxyphenyl)-2-methylpropan-1 –one compound of formula-14 with vinyl magnesium bromide in tetrahydrofuran to provide compound of formula-15.

6. A process for the preparation of crystalline form-B of 3-[(li?,2i?)-3-(dimethylamino)-1 - ethyl-2-methylpropyl]phenol hydrochloride compound of formula-la, comprising of:

a) Dissolving the 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1 in ethyl acetate,

b) filtering the reaction mixture,

c) adjusting pH of filtrate to 1-2 with ethyl acetate-HCl,

d) stirring the reaction mixture,

e) filtering the precipitated solid,

f) drying the solid to get crystalline form-B of compound of formula-1 a.

7. A process for the preparation of 3-[(li?,2/?)-3-(dimethylamino)-l-ethyl-2-methylpropyl] phenol compound of formula-1, comprising of:

a) Hydrogenating the (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15 in presence of a suitable metal catalyst and hydrogen gas in a suitable solvent to provide (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3 -ol compound of formula-16,

Formula-16 b) dehydrating the compound of formula-16 in-situ by treating it with a suitable dehydrating agent in a suitable solvent to provide (R,Z)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-l-amine compound of formula-17, Formula-17

c) reducing the compound of formula-17 in-situ with a suitable reducing agent in a suitable solvent to provide (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-8,

Formula-8 d) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide compound of formula-1.

8. The process according to claim 7, wherein,

In step-a) the suitable metal catalyst is selected from Pd, Pt, Ru and Rh catalysts such as Pd, Pd-C, Pd(OH)2, Pd(OAc)2, PdCl2, Pt, PtO2, Pt-C, Ru-C and Rh-C; and Raney-Ni; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and alcoholic solvents;

In step-b) the suitable dehydrating agent is selected from inorganic acids, organic acids, acid anhydrides, phosphorous pentoxide; phosphoryl chloride; phosphoric acid; and dicyclohexyl carbodiimide; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents;

In step-c) the suitable reducing agent is selected from Ru, Rh metal catalysts such as Ru-C and Rh-C in presence of hydrogen; Raney-Ni in presence of hydrogen; sodium borohydride; and Pd, Pt, Ru, Rh and Re catalysts such as Pd, Pd-C, Pd(OH)2, PdCl2, Pd(OAC)2, Pt, Pt-C, PtO2, Ru-C, Rh-C, ReIO2(PPh3)2, ReOCl3(PPh3)2, ReOCl3(dppm), and Re2O7 in presence of hydrogen source such as silane and sodium borohydride; and the silane is selected from dimethylphenyl silane, phenyl silane, triethyl silane, triphenyl silane and poly methylhydrosiloxane; and the suitable solvent is selected from ester solvents,

ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof; preferably hydrocarbon solvents, alcoholic solvents, chloro solvents and polar aprotic solvents; and In step-d) the suitable demethylating agent is selected from hydrobromic acid optionally in combination with carboxylic acid such as formic acid, acetic acid; methane sulfonic acid, methionine, diisobutyl aluminium hydride, pyridine chloride, lewis acids like aluminium chloride, boron tribromide and mixtures thereof; and the suitable solvent is selected from is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents and chloro solvents.

9. A process for the preparation of 3-[(li?,2i?)-3-(dimethylamino)-l-ethyl-2-methylpropyl] phenol compound of formula-1, comprising of:

a) Acylating the (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15 with a suitable acylating agent in presence or absence of a base in a suitable solvent to provide its corresponding acyl derivative compound of general formula-18,

Formula-18

b) hydrogenating the compound of general formula-18 in-situ in presence of a suitable metal catalyst and hydrogen in a suitable solvent to provide (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethyl pentan-1-amine compound of formula-8,

c) O-demethylating the compound of formula-8 with a suitable demethylating agent in a suitable solvent to provide compound of formula-1.

10. The process according to claim 9, wherein,

In step-a) the suitable acylating agent used is selected from anhydrides and halides of acetic acid, phenyl acetic acid, chloro acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, benzoic acid, chlorobenzoic acid, terephthalic acid,

phthalic acid, succinic acid, mono C1-C4 alkyl esters of succinic acid, oxalic acid, mono C1-C4 alkyl esters of oxalic acid such as ethyl oxalyl chloride and methyl oxalyl chloride, and mixed anhydride of formic acid such as ethyl chloroformate,

methyl chloroformate and acetyl salicyloyl chloride; the base is inorganic or organic base; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof,

preferably ether solvents and alcoholic solvents; In step-b) & c) the suitable metal catalyst, demethylating agent and solvent used are same as defined in step-(a) and step-(d) of claim 8 respectively.