WO2011092719A2

WO2011092719A2 - Process for the preparation of l-phenyl-3-dimethylaminopropane derivatives

Info

Publication number: WO2011092719A2
Application number: PCT/IN2011/000060
Authority: WO
Inventors: Shekhar Bhaskar Bhirud; Perminder Singh Johar; Ekta Sharma; Danish Jamshad; Ramkaran Prajapaty
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2010-02-01
Filing date: 2011-01-28
Publication date: 2011-08-04
Also published as: WO2011092719A3

Abstract

Process for preparing 1-phenyl-3-dimethylaminopropane derivatives of formula (I), and pharmaceutically acceptable salts thereof from intermediate of formula (II) are provided, wherein R₁ can be selected from -OR₂, halo, -CH₂OR₂, -SR₂, SOR₂, SO₂R₂, -SO₃H, -NO₂, -NR₂R₂', - CONR₂R₂ ', and the like; R ' can be selected from hydrogen, alkyl, aryl, aralkyl, alkaryl, heteroaryl, and the like; or R₂ and R2 ' can be same or different and can be selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl,-OR₃, - COR₃, -PO₃(R₃R₁) wherein R₁ and R₄ can be same or different and can be selected from alkyl, aryl, aralkyl, heteroaryl and the like.

Description

"Process for the preparation of l-phenyl-3-dimethylaminopropane derivatives"

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of l-phenyl-3-dimemylaminopropane derivatives of formula I, cally acceptable salts thereof.

Formula I

Specifically, present invention provides a process for the preparation of tapentadol of formula la,

and its pharmaceutically acceptable salts thereof via novel intermediates.

BACKGROUND OF THE INVENTION

Tapentadol of formula la,

Formula la

is marketed as its hydrochloride salt under the trade name Nucynta and is chemically known as 3-[(lR,2R)- 3-(dimethylamino)- 1 -ethyl-2-methylpropyl]phenol.

It is a centrally-acting analgesic with a unique dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor. μ-Opioid agonists are drugs that bind to and activate μ -opioid receptors in the central nervous system. These drugs modify sensory and affective aspects of pain, inhibit the transmission of pain at the spinal cord and affect activity at parts of the brain that control how pain is perceived. Norepinephrine reuptake inhibitors are a type of central nervous system medication that increases the level of norepinephrine in the brain by inhibiting its re-absorption into nerve cells; these compounds have analgesic properties.

Tapentadol and its analogues are first disclosed in US patent USRE 39,593 (reissue of US patent

6,248,737). According to the process disclosed in above patent, tapentadol, is prepared by process as shown in the following scheme:

The preparation of tapentadol starts from reaction of 3-bromoanisole with l^imethylamino-2- methylpentan-3-one to form racemic tertiary alcohol intermediate, which then resolved by chiral HPLC. The resolved intermediate is then converted into corresponding chloride compound, followed by reduction with zinc borohydride, zinc cyanoborohydride or tin cyanoborohydride and then finally converted into tapentadol by demethylation with hydrobromic acid. The process involves formation of hydrochloride salts of the intermediates which are then used in the next stage. The hydrochloride formation of the intermediates take place in the presence of trimethylchlorosilane which is highly flammable liquid and being hazardous not advisable to use in the industrial scale. The other disadvantage of the above process is resolution by the chiral HPLC, which is not amenable for commercial synthesis on industrial level.

US patent 7,417,170 discloses a process for preparing racemic 3-(3- methoxyphenyl)-N,N,2- trimemylpentanamine, an intermediate of tapentadol by reaction of (2S,3S)-1 -(dimethyl -amino)-3-(3- methoxyphenyl)-2-methyl-3-pentanol with an acid to form a mixture of cis and trans isomer of alkene intermediate, the resulting mixture is then hydrogenated to form a mixture of (2R,3R) and (2R,3S)-3-(3- memoxyphenyl)-N,N,2-trimemylpentanamine as outlined below.

(2S-3S) (ZM2R)-HEM2R) (2R^R) (2R S) US patent application 2006/0167318 discloses a process for preparing racemic 3-(3-methoxyphenyl)-N,N,2- trimethylpentanariiine, an intermediate of tapentadol, by dehydrating corresponding (2S,3S) tertiary alcohol intermediate, followed by reduction of resulting alkene intermediate using heterogeneous catalyst to form a mixture of (2R,3R) and (2R,3S)-3-(3-memoxyphenyl)-N,N,2-trimemylpentananiine as outlined below.

(2R,3R) (2IUS)

The above disclosures are silent about the conversion of racemic mixture of 3-(3- methoxy phenyl)-N,N,2- trimelhylpentanamine to tapentadol, the final API.

PCT publication WO 2008/012283 discloses a process for the preparation of (2R,3R)-3-(3- memoxyphenyl)-N,N,2-trimemylpentanamine, an intermediate of tapentadol by treating corresponding hydroxy compound with acid chloride, ethyl oxalyl chloride or trifluoro acetic acid anhydride, then converted to (2R,3R)-3-(3-memoxyphenyl)-N,N,2-trimemylpentanamine or its acid addition salts as outlined below.

In view of the above, there is an urgent need to develop a cost effective and industrially advantageous process for the synthesis of l-phenyl-3-dimemylaminopropane derivatives. Thus, present invention fulfills the need in the art and provides an industrially advantageous process for the synthesis of l-phenyl-3- dimethylaminopropane derivatives in particular tapentadol and its pharmaceutically acceptable salts thereof that do not involve chiral chromatographic technique for the separation of isomers.

OBJECTIVE OF THE INVENTION

It is the principal objective of the present invention to provide an industrially advantageous process for preparing l-phenyl-3-dimemylaminopropane derivatives of formula I, including its isomers, enantiomers, diastereomers, racemates, solvates, hydrates or pharmaceutically acceptable salts thereof using novel intermediates.

Another objective of the present invention is to provide a process for preparing tapentadol of formula la, its pharmaceutically acceptable salts thereof using novel intermediates.

Another objective of the present invention is to provide novel intermediates and process for preparing the same, which can be useful in the preparation of l-phenyl-3-dimemylaminopropane derivatives of formula I and its pharmaceutically acceptable salts thereof.

Another objective of the present invention is to provide novel chiral intermediates.

Still another objective of the present invention is to provide a process for the preparation of (R)(R)-isomer of acid intermediates by the resolution of respective racemic intermediate.

Yet another objective of the invention is to provide a process for the preparation of l-phenyl-3- dimethylaminopropane derivatives of formula I and its pharmaceutically acceptable salts thereof by demethylation of methoxy intermediate or salts thereof.

SUMMARY OF THE INVENTION

Accordingly, present invention provides a novel and industrially advantageous process for the preparation of l-phenyl-3-dmiemylaminopropane derivatives of formula I,

Formula I

including its isomers, enantiomers, diastereomers, racemates, solvates, hydrates or pharmaceutically acceptable salts thereof.

According to one embodiment, present invention provides a process for the preparation of l-phenyl-3- dimethylaminopropane derivatives of formula I, or its isomers, enantiomers, diastereomers, racemates, solvates, hydrates or pharmaceutically acceptable salts thereof, comprising the steps of:

a), reducing an intermediate of formula Π,

Formula II

wherein R, can be selected from -OR₂, halo, -CH₂OR₂, -SR₂, SOR₂, -S0₂R₂, SO₃H, -N0₂, -NR₂R₂ ', - CONR₂R₂ ', carboxylic esters, sulfonate esters or phosphate esters and the like; R ' can be selected from

hydrogen, alkyl, aryl, aralkyl, alkaryl, heteroaryl,

HN-R4_; and the like; or

OR ' can be selected from ~NR₂R₂ '; or

R₂ and R₂ ' can be same or different and can be selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl,- OR₃, -COR₃, -POjfRjR_f) wherein R₃ and R4 can be same or different and can be selected from alkyl, aryl, aralkyl, heteroaryl and the like

using a suitable reducing agent;

b). optionally, isolating aldehyde intermediate of formula ΠΙ;

Formula III

wherein Rj is as defined above

c). recovering hydroxyl intermediate of formula IV from the reaction mixture;

Formula IV

wherein R_/ is as defined above

d). converting the hydroxyl moiety of intermediate of formula IV into a good leaving group to obtain intermediate of formula V;

Formula V

wherein R_/ is as defined above; and LG is good leaving group and can be selected from substituted and unsubstituted alkyl sulfonate, substituted and unsubstituted aryl sulfonate or halogen, -OCOR3, - OPOR₃R , -OSOR3, -SCO₂R3, -OCSR₃ and the like and R₃ and R4 are same or different and are as defined above

in the presence of suitable reagent;

e) . condensing intermediate of formula V with substituted amine of formula VI, R* Formula VI wherein R5 and R4 can be same or different and independently can be selected from hydrogen, alkyl, aryl, aralkyl, alkaryl, -SO₂R₃, -S0₂Ar, -COR3, -OPOR₃R₄, (wherein R₃ andR₄ are as defined above); R$ and Re can be combined to form a five membered heterocyclic ring or five membered heterocyclic ring fused with six membered ring, preferably ring can be pyrrolidine-2,5-dione; substituted or unsubstituted isoindole-1 ,3-dione; substituted or unsubstituted l,l-dioxo-l,2-dihydro- benzo[dJisothiazol-3-one and the like, wherein substituent can be alkyl, aryl, aralkyl or alkaryl and the like

or salts thereof in the presence of a suitable base to form an intermediate of formula VH; and

Formula Vn

wherein Ri , R5 and R^ are as defined above

f . converting the intermediate of formula VII or salts thereof to l^henyl-3-dimemylaminopropane derivatives of formula I or pharmaceutically acceptable salts thereof.

According to another embodiment, present invention provides a process for the preparation of l-phenyl-3- dimethylaminopropane derivatives of formula I, or pharmaceutically acceptable salts thereof, comprising the steps of:

a) , reducing intermediate of formula Π using a suitable reducing agent;

b) . optionally, isolating aldehyde intermediate of formula ΠΙ,

c) . recovering hydroxyl intermediate of formula IV from the reaction mixture;

d) . converting the hydroxyl moiety of intermediate of formula IV into a good leaving group, in the presence of a suitable reagent; to obtain an intermediate of formula V

e) . condensing intermediate of formula V with NN-dimemylamine or salts thereof in presence of a suitable base to form compound of formula VIII; and

Formula VIII

wherein Rj is as defined above

f). converting intermediate of formula VIII or salts thereof to l-phenyl-3-dimethylaminopropane derivatives of formula I or pharmaceutically acceptable salts thereof.

According to still another embodiment, the l-phenyl-3-dimemylaminopropane derivative of formula I prepared by processes of the present invention is tapentadol of formula la,

Formula la

or its pharmaceutical acceptable salts thereof, using desired enantiomer of the novel intermediates or by resolving the racemic mixture of l-phenyl-3-dimemylaminopropane derivative of formula I.

According to one embodiment, present invention provides a process for the preparation of tapentadol of formula la or pharmaceutically acceptable salts thereof, comprising the steps of:

a), converting an acid intermediate of formula Ha,

CH₃ Formula Ila

in to hydroxyl intermediate of formula IVa;

CH₃ Formula IVa

b). reacting hydroxyl intermediate of formula IVa with a suitable reagent to form intermediate of formula Va;

c¾ Formula Va

wherein LG is a good leaving group which are as defined above

c). condensing intermediate of formula Va with N,N-dimethylamine or salts thereof in the presence of suitable base to form intermediate of formula Villa,

Formula Villa

or salts thereof; and

d). converting intermediate of formula Villa or salts thereof into give tapentadol or its pharmaceutically acceptable salts thereof.

According to another embodiment, present invention provides a process for the preparation of a compound of formula I, or salts thereof

Formula I

which comprises step of demethylating methoxy intermediate of formula VHTb,

Formula Vlllb

using a suitable demethylating agent.

According to another embodiment, present invention provides a process for conversion of intermediate of formula II in to hydroxyl intermediate of formula IV, comprising the steps of:

a) , reducing acid intermediate of formula Π using a suitable reducing agent; and

b) . isolating hydroxyl intermediate of formula IV there from.

According to another embodiment, present invention provides a process for the conversion of acid intermediate of formula

Formula lib

in to hydroxyl intermediate of formula IV, comprising the steps of:

a), esterifying acid intermediate of formula lib to form ester intermediate of formula Hb'; and

Formula lib' wherein R " is. alkyl, aryl, aralkyl, alkaryl,

. and R₃ and R4 are as defined above

b). reducing ester intermediate of formula lib' to form hydroxyl intermediate of formula IV.

According to another embodiment, present invention provides a process for the conversion of acid intermediate of formula lib in to hydroxyl intermediate of formula IV, comprising the steps of:

a), activating the carboxyl moiety of intermediate of formula lib to form activated intermediate of formula,

wherein Xis hal , - O-COR3, -O -SO₂R3, , wherein R3 is as defined above

b). reducing activated intermediate of acid intermediate of formula lib to form hydroxyl intermediate of formula IV.

According to another embodiment, present invention provides a process for preparation of acid intermediate of formula Ha,

CH₃ Formula Ha

by resolution of racemic form of compound of formula lib,

Formula lib

According to yet another embodiment, present invention provides a process for the preparation of intermediate of formula

Formula Π

wherein R/ and R ' are as defined above or its isomers, enantiomers, diastereomers, racemates, solvates, hydrates or salts thereof, comprising the steps of:

a), hydrolysing the intermediate of formula ΓΧ;

Formula IX

wherein Ri is as defined above

with a suitable hydrolyzing reagent; and

b). isolating the compound of formula II there from.

According to yet another embodiment, present invention provides a process for the preparation of intermediate of formula II or its isomers, enantiomers, diastereomers, racemates, solvates, hydrates or salts thereof starting from compound of formula X.

Formula X

wherein Rj is as defined above; R7, Rg can be same or different and can be independently selected from - CN, -CONR₂R₂ ' -COOR₉, -COOR9 ' ; -COSR9; -SO2R₉ or R₇ and Rs can be combined together to form six membered heterocyclic ring selected from l,3-dioxane-4,6-dione or 2,2-dialkyl-l ,3-dioxane-4,6-dione and the like; provided both R7 and Rs can not be -SO₂R₉

Rg, Rg ' can be same or different and is same as that of R '; R' is as defined above

According to one preferred embodiment, present invention provides a process for the preparation of intermediate of formula II or salts thereof, comprising the steps of :

a), reacting dicyano compound of formula Xa;

Formula Xa

wherein R_/ is as defined above

with a suitable hydrolyzing and decarboxylating reagent; and

b). optionally, isolating one or more corresponding intermediate of general formula XI,

Formula XI

wherein Ri is as defined above; Rjo and Rio ' can be same of different and can be independently selected from hydrogen, -CN, -CONH₂, -COOH provided both can not be -CNor hydrogen

c). isolating intermediate of formula Π there from.

According to one more preferred embodiment, present invention provides a process for the preparation of intermediate of formula lie (wherein R' is hydrogen),

Formula lie

wherein R_/ is as defined above

or its isomers, enantiomers, diastereomers, racemates, solvates, hydrates or salts thereof, comprising the steps of :

a), reacting dicyano compound of formula Xa;

Formula Xa

wherein Ri is as defined above

with a suitable hydrolyzing and decarboxylating reagent; and

b). isolating intermediate of formula Π there from.

According to another preferred embodiment, present invention provides a process for the preparation of intermediate of formula Π or salts thereof, comprising the steps of:

a), reacting the cyano ester compound of formula Xb;

Formula Xb

wherein Rj and R9 is as defined above

with a suitable hydrolyzing and decarboxylating reagent; and

b). isolating intermediate of formula Π there from. According to another preferred embodiment, present invention provides a process for the preparation of intermediate of formula Π or salts thereof, comprising the steps of :

a), reacting the diester compound of formula Xc;-

Formula Xc whereinRi, Rg and R₉ ' are as defined above

with a suitable decarboxylating and hydrolyzing reagent; and

b). isolating intermediate of formula Π there from.

According to yet another preferred embodiment, present invention provides a process for the preparation of intermediate of formula Π or salts thereof, comprising the steps of :

a), reacting the compound of formula Xd;

Formula Xd

wherein Ri, R₂ and R2 ' are as defined above

with a suitable hydrolyzing and decarboxylating reagent; and

b). isolating intermediate of formula Π there from.

According to still another preferred embodiment, present invention provides a process for the preparation of intermediate of formula Π or salts thereof, comprising the steps of :

a), reacting the compound of formula Xe;

p J CrN^Rl

^^j-COSR,

CH₃ Formula Xe

wherein Rj and R₉ are as defined above

with a suitable hydrolyzing and decarboxylating reagent; and

b). isolating intermediate of formula Π there from.

DETAILED DESCRIPTION OF THE INVENTION

As used herein "compound of formula Γ', l-phenyl-3-dimemylaminopropane derivatives of formula I as well as "all the intermediates i.e intermediate of formulae II, lib, lib', He, III, IV, V, VI, VII, VIII, Vlllb, EX, X, Xa, Xb, Xc, Xd, Xd, Xe, Xi etc." used herein include their isomers, enantiomers, diastereomers, racemates, salts, solvates, and hydrates thereof. The present invention provides a process for preparation l-phenyl-3-dimethylaminopropane derivatives of formula I, or pharmaceutically acceptable salts thereof using novel intermediates.

Specifically present invention provides a process for preparation of tapentadol of formula la or its pharmaceutically acceptable salts thereof using intermediate of formula Π or from corresponding desired isomer of the novel intermediates and/or salts thereof or by performing resolution after the synthesis of racemic final compound.

According to one embodiment, present invention provides a process for the preparation of l-phenyl-3- dimemylaminopropane derivatives of formula I by initially converting intermediate of formula Π in to hydroxyl intermediate of formula IV which forms a novel part of the invention.

According to one way, hydroxyl intermediate of formula IV can be prepared by the reduction of the intermediate of formula Π through the optional isolation of aldehyde intermediate of formula ΙΠ.

Generally, process involves the reaction of intermediate of formula II with a suitable reducing agent at a temperature of 0 °C to 150 °C for few minutes to few hours, preferably till the completion of the reaction. The reagent employed for the reaction can be selected from the reducing reagents known in the art that can be effectively used for the purpose of reduction of acid or ester or amide functionality to alcohol. Preferably, reducing reagent includes boron compounds such as borane, borane complexes, borane dimethylsulfide; lithium aluminium hydride, vitride, sodium borohydride and the like with or without catalyst. The reduction reaction can be carried out by hydrogenation using hydrogen source such as nascent hydrogen in the presence of a suitable catalyst that includes but not limited to transition metal catalyst such as nickel, palladium, platinum and the like with or without support (carbon) or as organometallic complexes. The presence or absence of solvent in the reaction mixture is not critical. The solvent employed for the reaction includes but not limited to straight chain, branched chain, cyclic aliphatic (Cs-io) or aromatic (C_6-1o) hydrocarbon solvents such as pentane, n-hexane, cyclo-hexane, n-heptane, toluene, ortho xylene, meta xylene, para xylene, ethyl benzene; C4__!o ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, cyclopentyl methyl ether; tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4 dioxane, 1,2 dimethoxy ethane, diphenyl ether, halogenated solvents such as dichloromethane, chloroform; C_2-io esters such as ethyl acetate, tertiary butyl acetate, isopropyl acetate; nitriles such as acetonitriles, propionitriles; Q. io alcohols such as methanol, ethanol, isopropanol and the like or mixture thereof. After the completion of the reaction, reaction mixture can optionally be quenched, whenever required. The suitable reagent employed to quench the reaction can be selected from any reagent that can eliminate unreacted or excess of the reducing agent left out in the reaction mixture. Quenching agent employed for the reaction can be selected from water; alcohol such as methanol; esters such as ethyl acetate; organic or inorganic acid or salts thereof. Hydroxyl intermediate of formula IV can be isolated from the reaction mixture or can be in situ used for the further reaction. The desired product can be isolated by any conventional methods known in the art for the isolation such as distillation, evaporation, filtration and the like. Specifically, the hydroxyl intermediate of formula IV can be isolated by removing the solvent from the reaction mixture followed by extraction with a suitable water immiscible solvent. Suitable solvent for the extraction includes Gno ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, straight chain , branched chain or cyclic aliphatic (Cs-io) hydrocarbon solvents such as pentane, n-hexane, cyclo-hexane, n-heptane; aromatic (C6- io)hydrocarbon solvents such as toluene, ortho-xylene, meta-xylene, para-xylene, ethyl benzene; C_2-8 esters such as ethyl acetate, methyl acetate, isopropyl acetate; halogenated solvents such as chloroform, dichloromethane; and the like or mixture thereof. The resulting organic layer can be optionally washed or treated with a suitable acid such as aqueous hydrochloric acid and/or water. Thereafter, product can be recovered from the resulting solution employing the methods known in the art such as distillation and the like.

Alternatively, intermediate of formula Π can be first converted to aldehyde intermediate of formula HI. The reaction can be carried out in single step or multistep depending upon the reaction condition and reagent employed. Thereafter, aldehyde intermediate of formula III can be converted to hydroxyl intermediate of formula IV. Aldehyde intermediate of formula ΙΠ can be isolated from the reaction by maintaining the suitable reaction condition such as amount of the reagent, temperature, reaction time as well as nature of reagent employed for the reaction. Preferably, the reagent employed for the conversion of intermediate of formula II to aldehyde intermediate of formula ΙΠ can be selected from metal borohydride such as sodium borohydride or derivative thereof; metal aluminium hydride such as lithium aluminium hydride and derivative thereof; Red-Al, L-selectride, Vitride, dibutyl aluminium hydride, diisobutyl aluminium hydride, Alane and the like. Reduction can be effectively carried out by hydrogenation using homogeneous or heterogeneous catalyst such as palladium, platinum, ruthenium, rhodium or other hydrogen donar agent such as ammonium formate can be employed. Further isolated aldehyde intermediate of formula III can be further reacted with a suitable reagent for few rninutes to few hours till the complete conversion to hydroxyl intermediate of formula IV. The reducing agent employed includes metal borohydride such as sodium borohydride or derivative thereof; metal aluminium hydride such as lithium aluminium hydride and derivative thereof; Red-Al, L-selectride, Vitride, dibutyl aluminium hydride, Alane and the like. Reduction can be effectively carried out by hydrogenation using homogeneous or heterogeneous catalyst such as palladium, platinum, ruthenium, rhodium or other hydrogen donar agent such as ammonium formate can be employed. Hydroxyl intermediate of formula IV, can be isolated from the reaction mixture by the conventional methods known in the art or as described above. In another way, hydroxyl intermediate of formula IV can be prepared from intermediate of formula II (wherein R ' is hydrogen) through esterification followed by reduction.

Generally, process involves esterification of acid intermediate of formula II (wherein R ' is hydrogen) using a suitable esterifying agent at a temperature of -20 to 150 °C, for few minutes to few hours, preferably till the completion of the reaction. Esterifying reaction can be carried out using a suitable alcohol of general formula R OH (wherein R" is as defined above other than hydrogen) in the presence of a suitable catalyst selected from Lewis acid such as borane trifluoride. diethyl ether complex; boric acid and the like; or acids such as carboxylic acids, sulfonic acids, phosphoric acid, sulfuric acid or derivative thereof and the like. The esterification reaction can be carried by activating the acid compound of formula II using a suitable reagent selected from acetic anhydride, thionyl chloride, boric acid and other reagents known in the art that can activate an acid functionality.

The activated acid compound can be then made to react with suitable alcohol of general formula R"OH in th& presence of suitable base. Base used for the reaction can be organic or inorganic base. Organic base can be trialkyl amine such as triethyl amine and the like. Inorganic base can be alkali or alkali metal hydroxide, alkoxide, hydride, carbonate, bicarbonate thereof such as sodium bicarbonate and the like.

Specifically, esterification reaction can be carried out using a suitable alcohol in the presence of catalyst at a temperature of -20 to 120 °C till the completion of esterification. Nature of the alcohol group depends upon the ester group to be introduced in the molecule and can be selected from the alcohol as defined above. After the esterification reaction, corresponding ester intermediate can be isolated from the reaction mixture using conventional method known in the art, preferably the ester intermediate can be extracted using a suitable solvent. The reaction mixture can be cooled either by reducing temperature or by the addition of water prior to extraction with a solvent. Ester intermediate can be recovered from the resulting solution by the removal of the solvent using suitable techniques such as distillation, evaporation and the like.

The ester intermediate thus prepared by either of the process can be then reduced to form hydroxyl intermediate of formula IV.

Generally, process involves the reaction of ester intermediate with a suitable reducing agent at a temperature of -15 °C to 150 °C for few minutes to several hours, preferably till the completion of the reaction. The reagent employed for the reduction can be selected from the reducing reagents known in the art that can be effectively used for the purpose of reduction of ester functionality to alcohol. Reducing agent, solvent and other reaction conditions are same as employed previously for the reduction. After completion of reaction, hydroxyl intermediate of formula IV can be isolated from the reaction mixture or can be used as such for further reaction. The desired product can be isolated by any conventional methods known in the art for isolation such as distillation, evaporation, and the like. In still another way, hydroxyl intermediate of formula IV can be prepared by the activation of carboxyl moiety of the intermediate of formula II (wherein R ' is hydrogen) using a suitable activating agent followed by reduction.

Generally, the process involves the activation of intermediate of formula Π (wherein R ' is hydrogen) using a suitable activating agent at a temperature of -20 to 120 °C, for few minutes to few hours, preferably till the completion of the reaction. Suitable reagent selected from thionyl halide such as thionyl chloride, thionyl bromide; phosphorus trihalides, phosphorus oxy halides, compound of general formula R'COX, R'S0₂X, R'NCN (wherein in R' is as defined above and X is halo group such as chloro, bromo, fluroro and the like) such as N,N-dicyclohexylcarbodiimide and other reagents known in the art that can activate an acid functionality. Intermediate of formula Π thus activated by the introduction of halo group can be further activated using imidazole and the like.

The solvent employed for the reaction includes aliphatic or aromatic hydrocarbon such as toluene; halogenated solvent such as dichloromethane, chloroform; ether such as tetrahydrofuran, methyl tertiary butyl ether, isopropyl ether and the like. Usually, reaction is carried out at a temperature of - 15 to 120 °C till the completion of the reaction. After the completion of the reaction, the activated intermediate can be isolated from the reaction mixture using suitable techniques or can be used in situ for the further reaction. The activated intermediate can be isolated by the removal of the solvent from the reaction mixture or can be proceed as such for the further reduction reaction.

Activated intermediate thus prepared can be then reduced to form hydroxyl intermediate of formula IV. Generally, process involves the reaction of the activated intermediate with a suitable reducing agent at a temperature of -20 °C to 120 °C for few minutes to few hours, preferably till completion of reaction. The reagent employed for reduction can be selected from the reducing agents known in the art that can be effectively used for the purpose of reduction of the activated group as described in present invention to alcohol. Reducing agent, solvent and other reaction conditions are same as employed previously for the reduction. After completion of reaction, hydroxyl intermediate of formula IV can be isolated from the reaction mixture or can be used as such for further reaction. The desired product can be isolated by any conventional methods known in the art for the isolation such as distillation, evaporation, and the like.

Intermediate of formula Π (including (R)(R), (R)(S), (S)(R), (S)(S) or mixture of two or more isomer in any proportion) can be converted to corresponding isomer of hydroxyl intermediate of formula IV by using any of the method using similar reaction condition as specified above.

Preferably, compound of formula Π (wherein Rj is OCH_3; and including (R)(R), (R)(S), (S)(R), (S)(S) or mixture of two or more isomer in any proportion) can be converted to corresponding hydroxyl intermediate of formula TV by any of the above process selected from direct reduction; intermediacy of aldehyde; by conversion of acid to ester intermediate followed by reduction; or through activated intermediate of acid intermediate of formula lib. Specifically, compound of formula Ila ((R)(R)- isomer of compound of formula II, wherein Ri is OCH$ and R ' is hydrogen, which may or may not contain other isomeric impurities) can be converted to hydroxyl intermediate of formula IVa by any of the above process which finally yield tapentadol of formula la or pharmaceutically acceptable salts thereof.

Hydroxyl intermediate of formula TV, thus prepared, by any of the above process, if desired, can be purified using a suitable solvent or any other purification method can be employed to enhance the purity and/or to remove impurities, present in the product.

Thereafter, hydroxyl functionality of intermediate of formula IV is converted to good leaving group to form intermediate of formula V using a suitable reagent, which also forms novel part of the invention.

Generally, the process for conversion of the hydroxyl moiety of intermediate of formula IV into a good leaving group involves its reaction with a suitable reagent, having a good leaving group, in an organic solvent at a temperature of about -20° C to about 150° C, for few rninutes to few hours, preferably till the completion of the reaction. The sufficient time period necessary for obtaining compound V will depend on the different parameters of the reaction such as reagent employed, nature of solvent and nature of compound itself. Preferably, reaction mixture is maintained for 0.5 hours to about 10 hours, more preferably till the completion of the reaction. Organic solvent employed for the reaction includes but not limited to group consisting of halogenated solvents such as chloroform, dichloromethane, C4-io ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2- methyl tetrahydrofuran, 1,4 dioxane, 1,2 dimethoxy ethane, diphenyl ether; straight chain , branched or cyclic or aliphatic (C5_io)or aromatic (C_5-1o) hydrocarbon solvents such as pentane, n-hexane, cyclo-hexane, n-heptane, toluene, ortho-xylene, meta-xylene, para-xylene, ethyl benzene; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile, propionitrile; polar aprotic solvents such as N,N-dimethylformamide, Ν,Ν-dimethyl acetamide, N-methyl 2-pyrrolidinone, dimethylsulfoxide, sulfolane and the like or mixture thereof. The reagent containing the leaving group can be selected from thionyl halide such as thionyl bromide or thionyl chloride; aliphatic sulfonyl halide such as methanesulfonyl chloride; and aromatic sulfonyl halide such as benzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, or p-toluenesulfonyl chloride; phosphorus oxy halide, phosphorus trihalide, phosphorus pentahalide, hydrogen chloride, hydrogen bromide, phosphorus compound of formula P(R)₃ [wherein R is alkyl or aryl or aryloxy] in combination with other reagent selected from CX₄, isocyanates and X₂ (wherein X is as defined above); such as triphenyl phosphine or P(OPh) in combination with CX₄ or isocyanate or chlorine gas; and the like with or without catalyst. It is advantageous to add a suitable base to the reaction mixture. Base used for the reaction can be an organic base or an inorganic base. Organic base is an amine selected from trialkylamine such as triethylamine, diisopropylethyl amine or other tertiary amines and the like. Inorganic base includes alkali or alkaline metal carbonate, bicarbonate, hydroxide, hydrides and alkoxides thereof such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium bicarbonate and the like or combination thereof. The reaction can be optionally carried out in the presence of a suitable catalyst which is selected from catalyst known in the art that can serve the purpose, preferably ^N.N-dimemylaminopyridine can be used in the reaction; or when the leaving group is a halogen such as chloride, a catalytic amount of potassium iodide or dimethylformamide is preferably added to the mixture. Intermediate of formula V can proceeded to the next step without isolation or may be isolated by any means known in the art such as removal of solvent by suitable techniques like distillation, evaporation etc. The compound V may be used directly in the next stage without any purification process or can be purified by employing suitable purification method.

Intermediate of formula IV (including (R)(R), (R)(S), (S)(R), (S)(S) isomer or mixture of two or more isomer in any proportion) can be converted to corresponding isomer of intermediate of formula V by using the similar reaction condition as specified above. Preferably, compound of formula IV (wherein Rj is OCH}_; and including (R)(R), (R)(S), (S)(R), (S)(S) or mixture of two or more isomer in any proportion) can be converted to corresponding compound of formula V. Specifically, intermediate of formula IVa ((R)(R)- isomer of compound of formula IV, wherein Ri is OCH3, which may or may not contain other isomeric impurities) can be converted to compound of formula Va which finally yield tapentadol of formula la or pharmaceutically acceptable salts thereof.

Further, present invention provides the reaction of compound of formula V with a substituted amine of formula VI or salts thereof to form compound of formula VII which also forms a novel part of the invention.

Generally, the process of converting compound V into compound of formula VII involves reaction of compound V with substituted amine of formula VI or salts thereof in the presence of a suitable base at a temperature of -20 to 150 °C for few minutes to several hours, preferably till completion of reaction. The salt of compound of formula VI that can be employed for the reaction includes organic salt or inorganic salt. Preferably hydrochloride salt of compound of formula VI is used for the reaction. Base used for the reactkln can be an organic base or an inorganic base. Organic base is an amine having general formula NRgR_bRc (wherein R_a, R_b, & Rc can be independently selected from hydrogen, straight, branched or cyclic Cj-₁0 alkyl, aryl, heteroaryl, aralkyl, alkaryl, substituted alkyl, substituted aryl, heteroaryl and the like) such as tertiary amines like trialkylamine (triethylamine, diisopropylethyl amine) and the like. Inorganic base includes alkali or alkaline metal carbonate, bicarbonate, hydroxide, hydrides and^' alkoxides thereof such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate; with or without additives and the like or combination thereof. Reaction can be carried out in the presence of a solvent which provides reaction media for the reaction. Solvents include water, polar aprotic solvents such as N,N-dimethylformamide, Ν,Ν-dimethyl acetamide, N-methyl 2-pyrrolidinone, dimethylsulfoxide, sulfolane; protic solvents such as water, CM_O alcohols such as methanol, ethanol, propanol, isopropanol, n- butanol, isobutanol, tertiary butanol; ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4 dioxane, 1,2 dimethoxy ethane, diphenyl ether ; halogenated solvents such as chloroform or dichloromethane; straight chain , branched or cyclic or aliphatic (C_5-io) or aromatic (Cs-io) hydrocarbon solvents such as alkane (pentane, n- hexane, cyclo-hexane, n-heptane, toluene, ortho xylene , meta xylene, para xylene, ethyl benzene); nitriles such as acetonitrile, propionitrile; and the like or mixtures thereof. Preferably, the reaction is carried out for 0.5 hours to about 24 hours, more preferably till the completion of reaction. The reaction can be advantageously carried out using a suitable base in the presence or absence of phase transfer catalyst which includes tetrabutylamoinum bromide, benzyl triethyl ammonium chloride, cetyl trimethyl ammonium bromide, quaternary phosphonium, PEG and the like to enhance the progress of the reaction. After the completion of the reaction, reaction mixture can be quenched, whenever required, using a suitable quenching agent employed selected from water, alcohols, organic acid or inorganic acid or salts thereof and the like. The intermediate of formula VII can be isolated from the reaction mixture or can be preceded as such for the further reaction. The desired product can be isolated by any conventional methods known in the art for the isolation such as distillation, extraction with a suitable solvent followed by removal of solvent and the like. The isolated intermediate of formula VII, if desired, can be purified using a suitable solvent or any other purification method can be employed to enhance the purity or to remove the presence of impurities in the product. The reaction can optionally be proceeded without isolation of compound of formula VII.

Intermediate of formula V (including (R)(R), (R)(S), (S)(R), (S)(S) isomer or mixture of two or more isomer in any proportion) can be converted to corresponding isomer of intermediate of formula VII by using the similar reaction condition as specified above. Preferably, compound of formula V (wherein Ri is OCH^and including (R)(R), (R)(S), (S)(R), (S)(S) or mixture of two isomer or more in any proportion) can be converted to corresponding compound of formula VII..

The compound of formula VII (including (R)(R), (R)(S), (S)(R), (S)(S) or mixture of two or more isomer in any proportion), thus prepared by any of methods, can be optionally converted to its acid addition salts.

The compound of formula VII or salts thereof can be converted to l^henyl-3-dimemylaminopropane derivatives of formula I and its pharmaceutically acceptable salts through the involvement of intermediate of formula Vila (a variant of compound of formula VII, wherein R3 and R₄ are hydrogen),

Formula Vila

wherein R I is as defined above

which is reacted with a suitable methylating agent to form intermediate of formula VIII. Compound of formula VIII is then finally converted to compound of formula I.

Generally, process involves conversion of substituted amine to primary amine by deprotection of the amine group. The process involves the removal of R₃ and R4 amine protecting group by any suitable reagent known in the art for deprotection of amine functional group. Usually process involves dealkylation, dearylation, de-aralkylation, dealkarylation, deacylation, desulfonylation or dephosphorylation reaction depending upon the nature of protecting group. The deprotecting reagent can be selected on the basis of the nature of group to be removed and are well known in the field of organic synthesis. Preferably, deprotecting reagent can be selected among borane compounds like borane trihalide; berylUum compounds such as berylUum dihalide; thiophenol, lithium diphenylphosphide, aluminium halide, thiol system, high molecular weight alkane or arene thiolate anions, trialkyl borohydride and its salts; thiophenol, sodium sulfide, isoamyl nitrite, mercaptans with alkali metal hydroxides and the like. The deprotection reaction can be carried out in the presence of acidic or basic conditions. Acid employed for the reaction includes carboxylic acid such as acetic acid and the like or inorganic acid. Base used can be organic or inorganic base. The deprotection reaction can also be effected by the hydrogenolysis of compound of formula VII using a suitable catalyst. The catalyst includes transition metals with or without support (carbon) such as palladium, platinum, nickel and the like. The reaction can take place over a wide range of temperature depending upon the nature of protecting group as well as on deprotecting reagent employed for the reaction to give compound of formula Vila. The compound of formula Vila can be isolated from the reaction mixture by the suitable methods known in the art or can be proceeded as such for the further reaction. The isolated intermediate of formula Vila can optionally be purified to enhance the purity or to remove the impurities, present in the intermediate of formula Vila.

The compound of formula Vila can be further converted to compound of formula VIII, using a suitable methylating reagent.

Generally, process involves reaction of compound of formula Vila with a suitable methylating reagent in a suitable solvent at a temperature of 0°C to room temperature till the completion of the reaction. The source of methyl group can be selected from any reagent known in the art for the methylation purpose. Preferably, the methyl group can be incorporated in compounds of formula Vila using a reagent selected from formaldehyde in combination with formic acid or metal hydride, methyl halide such as methyl iodide, methyl chloride, methyl bromide; dimethyl sulfate; methyl sulfates, dimethyl carbonate, trimethyl phosphate, methyl phosphates and the like. The solvent employed for the reaction is chosen on the basis of the reagent employed, preferably suitable solvent includes ethers, aromatic or aliphatic hydrocarbons, halogenated solvents, esters, ketones, nitriles, aprotic solvents such as dimethylsulfoxide, dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, sulfolane and the like or mixtures thereof. It is advantageous to add a suitable base to the reaction mixture. Suitable base can be organic or inorganic base. Organic base includes aliphatic or aromatic amine such as trialkylamine like triethylamine, cyclic amine, aryl amine and the like. Inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, hydride and alkoxide thereof. The compound of formula VIII can be isolated f om the reaction mixture by using any conventional technique known in the art or used as such for the further reaction. The compound of formula VIII can be optionally purified to increase the purity of the compound as well as to minimize the presence of impurities.

Alternatively, the compound of formula VIII can be prepared directly from compound of formula V by the reaction with N;N-dimethylamine or salts thereof in the presence of base at a temperature of -20 to 170 °C for few minutes to several hours, preferably till the completion of the reaction. The salts of N,N- dimethylaminee employed for the reaction can be organic or inorganic salt, preferably N,N-dimethylamine hydrochloride. The reaction can be advantageously carried out using a suitable base in the presence or absence of phase transfer catalyst. The solvent, base and phase transfer catalyst employed and reaction conditions are same as that of as described in the condensation of compound of formula V with substituted amine of formula VI. After the completion of the reaction, reaction mixture can be quenched, whenever required. The quenching agent employed for the reaction can be selected from water, alcohols, organic or inorganic acid or salts thereof and the like. The intermediate of formula VIII can be isolated from the reaction mixture or can be used in situ for the further reaction. The desired product can be isolated by any conventional methods known in the art for the isolation such as distillation and the like. Specifically, the compound of formula VIII can be isolated from the reaction by extraction with a suitable solvent such as ether such as isopropyl ether, methyl tert-butyl ether, 2-methyl tetrahydrofuran; halogenated solvents such as dichloromethane, chloroform; aliphatic or aromatic solvents such as toluene, cyclohexane, xylene, ethyl benzene and the like. Thereafter, product can be recovered from the resulting solution by either distillation, evaporation or precipitation, crystallization and the like. The isolated intermediate of formula VHI, if desired, can be purified using a suitable solvent or any other purification method can be employed to enhance the purity or to remove the presence of impurities in the product. Intermediate of formula VIII (including (R)(R), (R)(S), (S)(R), (S)(S) isomer or mixture of two or more isomer in any proportion) can be prepared from intermediate of formula V by condensation with N,N- dimethylamine or salts thereof using the similar reaction condition as specified above. Preferably, compound of formula Vlllb (a variant of compound of formula VIII, wherein Rj is OCH}_; including (R)(R), (R)(S), (S)(R), (S)(S) or mixture of two or more isomer in any proportion) can be prepared from corresponding isomer of intermediate of formula V. Specifically, intermediate of formula Villa ((R)(R)- isomer of compound of formula VIE, wherein R_/ is OCH₃, which may or may not contain other isomeric impurities) can be prepared from compound of formula Va which finally yield tapentadol of formula la or pharmaceutically acceptable salts thereof.

The compound of formula VHI (including (R)(R), (R)(S), (S)(R), (S)(S) isomer or mixture of two or more isomer in any proportion), thus prepared by any of methods, can be optionally converted to its acid addition salts.

Generally, the compound of formula VIII can be reacted with a suitable acid in a suitable solvent at -20 to 170°C for few minutes to few hours, till the completion formation of salt. Suitable acid employed can be chiral or achiral acid. Acid used in the reaction can be organic or inorganic acid and can be used in the form of aqueous solution, concentrated, in mixture with a solvent or solvent saturated with a suitable acid and the like. Organic acid includes carboxylic acid, sulfonic acid, alkyl phosphonic acid, aryl phosphonic acid and the like. Inorganic acid includes hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid and the like. Preferably, suitable acid employed is hydrochloric acid either in the aqueous form or in mixture with a suitable solvent such as ethereal hydrochloride (isopropyl ether hydrochloride); alcoholic hydrochloride (methanolic hydrochloride) or any other source of hydrochloric acid, ammonium chloride and the like or combination thereof. The acid addition salts of compound of formula VHI, thus prepared can be converted directly to l-phenyl-3-dimethylaminopropane derivatives of formula I and its pharmaceutically acceptable salts thereof or can be isolated from the reaction mixture by suitable techniques known in the art such as filtration, centrifugation, decantation and the like.

The present invention also provides conversion of compound of formula VIII (including (R)(R), (R)(S), (S)(R), (S)(S) isomer or mixture of two or more isomer in any proportion) to l-phenyl-3- dimethylaminopropane derivatives of formula I and its pharmaceutically acceptable salts thereof by the conversion of Ri group to hydroxy group provided reaction conditions employed will not affect the other functionalities of compound of formula VIII.

In one variant, the compound of formula VIII {wherein Rj is OR₂, wherein R₂ is as defined above) has structure of formula VIIIc,

Formula Villa

wherein R₂ is as defined above

or salts thereof and can be converted to l-phenyl-3-dimethylaminopropane derivatives of formula I by deprotection of O-protecting group by the methods known in the art or by the methods as described below. Generally, deprotection reaction involves the removal of R₂ group by any suitable reagent known in the art for deprotection of 0-protecting group. Usually process involves dealkylation, dearylation, de-aralkylation or desulfonylation or dephosphorylation or deacylation reaction depending upon the nature of hydroxy protecting group. The deprotecting reagent can be selected based on the nature of R₂ group that effectively cleave ether linkage and are well known in the field of organic synthesis. Preferably, the deprotecting reagent includes boron compounds like borane trihalide; beryllium compounds such as beiyllium dihalide; thiophenol, lithium diphenylphosphide, aluminium halide thiol system, high molecular weight alkane or arene thiolate anions, trialkyl borohydride and its salts; thiophenol, sodium sulfide and the like; silyl compounds such as trimethyl silyl halides with sodium iodide in nitrile solvents; hydrobromic acid, hydrochloric acid (aqueous, concentrated or gaseous); du^obutylaluminium hydride and the like. It is advantageous to perform deprotection using hydrochloric acid in combination with alkali metal halide such as potassium iodide or sodium bromide. The deprotection reaction may also be effected by hydrogenolysis of compound of formula VIIIc using a suitable catalyst. The catalyst includes transition metals with or without support (carbon) such as palladium, platinum, nickel and the like. The reaction can take place over a wide range of temperature depending upon the nature of R₂ group as well as on deprotecting reagent employed for the reaction.

Specifically, l-phenyl-3-dimethylaminopropane derivatives of formula I or pharmaceutically acceptable salts thereof can be prepared by the demethylation of compound of formula VI lib (a variant of compound of formula VIII, wherein Ri is OQ¾_; and including (R)(R), (R)(S), (S)(R), (S)(S) or mixture of two isomer or more in any proportion) and forms the novel part of the invention.

Typically, demethylation reaction involves removal of methyl group by any suitable reagent known in the art for demethylation. The reagent used for demethylation can be selected from any reagent known in the art that effectively cleave the ether linkage. Preferably, reagent includes high molecular weight alkane or arene thiolate anions such as ethanethiol, dodecanethiol or sodium sulfide with or without trimethyl silyl chloride or aluminium halide; boron trihalide, boron trihalide-dialkyl sulfide complex; aluminium halide, di-isobutyl aluminium hydride, tri isobutyl aluminium hydride; metal halide such as lithium iodide in combination with 2,4,6-collidine, lithium chloride in dimethylformamide, lithium triethyl borohydride, lithium tri sec-butyl borohydride; sodium iodide in combination with trimethyl silyl chloride; or sodium iodide, sodium bromide, potassium iodide in combination with inorganic acid such as hydrochloric acid.; pyridine or salts thereof such as pyridine hydrobromide; hydrobromic acid with or without carboxylic acid such as formic acid, acetic acid and the like or combination thereof. Reaction can be carried out optionally in an inert atmosphere. The reaction can take place over a wide range of temperature depending upon the nature of demethylating reagent employed for reaction. The reaction can be carried out using suitable solvents such as polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethyl acetamide, N- methyl 2-pyrrolidinone, dimethylsulfoxide, sulfolane; protic solvents such as water, Q.io alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tertiary butanol; Gno ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2- methyl tetrahydrofuran, 1,4 dioxane, 1,2 dimethoxy ethane, diphenyl ether, halogenated solvents such as chlorbform or dichloromethane; straight chain , branched or cyclic or aliphatic (C_5-io) or aromatic (Cs-io) hydrocarbon solvents such pentane, n-hexane, cyclo-hexane, n-heptane, toluene, ortho xylene , meta xylene, para xylene, ethyl benzene; nitriles such as acetonitrile, propionitrile; C_2-8 esters such as ethyl acetate, methyl acetate, isopropyl acetate; C_3-8 ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; and the like or mixture thereof. After the completion of the reaction, reaction mixture was neutralized by the addition of a suitable base followed by extraction of product with a suitable solvent. Suitable base can be organic base or inorganic base. Organic base can be an amine having formula NRaRbRc (wherein Ra, Rt» and Rc are as defined above) such as ammonia, triethylamine, diisopropyl ethyl amine; inorganic base includes alkali or alkaline metal hydroxide, carbonates or bicarbonates thereof such as sodium carbonate, sodium bicarbonate, sodium hydroxide, hthium carbonate, hthium bicarbonate, hthium hydroxide, potassium hydroxide, potassium carbonate, potassium bicarbonate and the like. Suitable solvent employed includes halogenated solvent such as dichloromethane, chloroform; ethers such as methyl tertiary butyl ether, 2-methyl tetrahydrofuran, tetrahydrofuran; esters such as ethyl acetate; alcohols such as methanol, ethanol, isopropanol, n-butanol and the like or mixture thereof. Compound of formula I can be isolated from the resulting organic layer by removal of solvent using techniques known in the art such as distillation of evaporation or can be converted in situ to pharmaceutically acceptable salts thereof.

Intermediate of formula VHIb (including (R)(R), (R)(S), (S)(R), (S)(S) isomer or mixture of two or more isomer in any proportion) can be converted to corresponding isomer of compound of formula I or pharmaceutically acceptable salts thereof. Specifically, intermediate of formula Villa ((R)(R)- isomer of compound of formula Vlllb, which may or may not contain other isomeric impurities) can be demethylated to yield tapentadol of formula la or pharmaceutically acceptable salts thereof.

In another alternate way, pharmaceutically acceptable salt of compound of formula I can be prepared directly from intermediate of formula VIII by in situ formation of compound of formula I.

Generally, process involves the reaction of intermediate of formula VIII with a suitable demethylating agent. Suitable demethylating agent and other reaction conditions employed for the reaction are same as described above. After completion of demethylation reaction, a suitable source of physiologically active acid (as defined above) is added to the reaction mixture. The desired pharmaceutically acceptable salt of compound of formula I can be isolated from the reaction mixture by techniques known in the art. Specifically, product can be extracted from the reaction mixture using a solvent in which product has more solubility. Suitable solvent employed includes halogenated solvent such as chloroform, dichloromethane, mixture of dichloromethane and tetrahydrofuran, n-butanol, ethyl acetate and the like. Salt thus can be isolated from the resulting organic layer by the removal of solvent using techniques known in the art such as distillation of evaporation. Preferably, tapentadol hydrochloride can be prepared.

Similarly, the intermediate of formula VIII (which includes any of the isomers such as (S)(S), (R)(R), (S)(R), (R)(S) or mixture thereof) or salts thereof can yield directly pharmaceutically acceptable salts of corresponding isomers of compound of formula I by demethylation using the same reagent and reaction condition as described above followed by salt formation. Preferably, intermediate of formula VHIa ((R)(R)- isomer of compound of formula VUIb) can be converted directly to pharmaceutically acceptable salts of tapentadol of formula la.

In another variant, the compound of formula VIII (wherein Rj is halo) has the structure of formula Vllld,

Formula Vllld

wherein Xis halo selected from chloro, bromo, iodo.fluoro

or salts thereof can be converted to compound of formula I using a reagent suitable for the purpose of conversion of halo group to hydroxy group by one of the following ways:

(i) direct conversion of halo group to hydroxy group; or

(ii) halo group is first converted to OR₂ group followed by deprotection to give hydroxy group.

Generally, the process involves the reaction of compound of formula Vllld or salts thereof with a suitable reagent that can displace halo group, at a temperature of 30 to 200 ° C for few minutes to few hours, preferably till the completion of the reaction. The suitable reagent employed for the reaction can be selected from any reagent known in the art that can result in displacement reaction of halo group with hydroxy group. Specifically, the reagent includes but not limited to alkali or alkaline metal hydroxide such as, sodium hydroxide, lithium hydroxide, potassium hydroxide and the like, with or without additives. The reaction can be carried out in a solvent that includes esters; ethers; aliphatic or aromatic hydrocarbon; nitriles; aprotic solvent such as dimethylsulfoxide, dimethylformamide, N-methylpyrroUdinone; sulfolanes and the like or mixture thereof. l-Phenyl-3-dimemylaminopropane derivatives of formula I or its pharmaceutically acceptable salts thereof can be isolated from the reaction mixture by using any conventional technique known in the art.

In other alternate way, the compound of formula VHId or salts thereof is first converted to compound of formula VIIIc then to 1 -phenyl-3-dimethylaminopropane derivatives of formula I.

Generally, the process involves the reaction of compound of formula VHId or salts thereof with a suitable reagent that can displace halo group with -OR₂ group (wherein R₂ is as defined above). The reaction is usually carried out at a temperature of 0 to 200°C for few minutes to few hours, preferably till the completion of the reaction. The suitable reagent employed for the reaction can be selected from any reagent known in the art that can convert halo group to -OR₂ group depending upon the nature of R₂ group. Specifically, the reagent includes but not limited to alkali or alkaline metal alkoxide, alkali or alkaline metal aryloxide, alkali or alkaline metal aralkoxide such as, sodium methoxide; with or without additives. The reaction can be carried out in a solvent that includes ethers, esters, aliphatic or aromatic hydrocarbon, aprotic solvents such as dimethylsulfoxide, dimethylformamide, N-methylpyrrolidinone; nitriles and the like or mixture thereof. The compound of formula VIIIc can be isolated from the reaction mixture by using any conventional technique known in art.

The compound of formula VIIIc, or salts thereof can be further converted to l-phenyl-3- dime&ylaminopropane derivatives of formula I or pharmaceutically acceptable salts thereof by the method already disclosed in the present invention or method known in the art.

Similarly, other Ri group can be converted to hydroxy group by processes as described in our co-pending application or by the methods known in the art.

In a more alternate way, the compound of formula Vila or salts thereof can be converted tol-phenyl-3- dimethylaminopropane derivatives of formula I though the intermediate of formula Vllb,

Formula VHb Generally, process involves the conversion of compound of formula Vila to intermediate of formula Vllb by converting R_{ group to -OH group by the method as described above depending upon the substituent. Thereafter, compound of formula VIIc- is selectively methylated using suitable methylating agent as described earlier, to give l^henyl-3-dimethylaminopropane derivatives of formula I.

According to yet another embodiment, the present invention provides a process wherein R_t group can be converted to hydroxy group at any intermediate stage or at the final stage.

l-Phenyl-3-dimemylaminopropane derivatives of formula I, preferably tapentadol of formula la, if isolated, can be optionally purified using a suitable purification method such as crystallization, slurry wash, washing or acid base treatment prior to conversion to pharmaceutically acceptable salts thereof. Suitable solvent employed for the purification includes alcohol, ester such as ethyl acetate; nitriles, ethers, aprotic solvent, ketones, aliphatic or aromatic hydrocarbon solvents, halogenated solvents and the like or mixture thereof. The final compound of the present invention contains two asymmetric carbon atoms in the molecule, and can thus form optical isomers. Similarly, the intermediates employed for synthesis also contain asymmetric carbon in their molecule, and can thus form optical isomers.

Accordingly, the present invention includes all possible stereo isomers of compound of formula I as well as of intermediates. It also includes not only racemic compounds or racemic mixtures thereof, but also all the optically active isomers as well. When a compound of formula I or its intermediate is desired as a single enantiomer, it may be obtained either by resolution of mixture of optical isomers of corresponding compounds or by a stereospecific synthesis from either optically pure starting material or any convenient intermediate. Where stereospecific synthesis techniques are employed or optically active compounds are employed as starting materials, individual isomers may be prepared directly, on the other hand, if a mixture of isomers is prepared, the individual isomers may be obtained by conventional resolution techniques known in the literature. Therefore, resolution of any of the intermediate during the synthesis can be carried out and proceeded to form specific isomer of l-phenyl-3-dimemylaminopropane derivatives of formula I, preferably tapentadol of formula la.

The methods for identifying and selecting the desired compounds are well known in the art for example, diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from each other by the selective crystallization of the diastereomeric salts with optically active acids or bases. Pure stereoisomers may also be prepared synthetically from the appropriate stereochemically pure starting materials, or by using stereoselective reactions.

According to another embodiment, present invention provides that l^henyl-3-dimethylaminopropane derivatives of formula I prepared by the processes of present invention has structure of formula la either by employing chiral synthesis using specific enantiomer of the intermediate (prepared by the resolution of the corresponding intermediate or by employing chiral starting compound) or by performing resolution at the final stage.

Resolving agent use for the resolution of the intermediate as well as of the final compound depends upon the functionality present in the corresponding compounds and can be performed by the general method known in the art. The resolving agent employed for the separation of isomers of the intermediates having amine functionality as well as for the final compound of formula I can be selected on the basis of nature of the intermediate or the final compound to be resolved. The resolving agent used for the resolution of the compound having amine functionality i.e. intermediate of formula VII including its variant or compound of formula I can be selected from the reagent known in the art for the same purpose and preferably can be selected from chiral acid of general formula,

R_a'R_b'R_c CCOOH

wherein R_a R and R_c- can be same or different and can be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkaryl, substituted or unsubstituted aralkyl and the like, preferably can be selected Ra , R and R_c- can be phenyl, naphthyl, or substituted naphthyl or substituted phenyl. Substituent can be heteroatom, or a functional group such as nitro, halo, ester, carbonyl, nitrile, hydroxy and the like. Specifically, the acid amongst (R) or (S)-mandelic acid, (R) or (S)- ibuprofen, (R) or (S)- naproxen, D or L- camphor sulfonic acid, D or L-tartric acid, D or L- dibenzoyl tartaric acid, D or L di-toluyl tartaric acid and the like can be employed for the resolution. Similarly, the resolving agent employed for the separation of isomers of the intermediates having acid functionality i.e. intermediate of formula Π (wherein R' is hydrogen), ester functionality i.e. intermediate of formula Π or alcoholic functionality i.e. intermediate of formula IV can be selected on the basis of nature of the intermediate to be resolved. The resolving agent used for the resolution of compound of formula Π either having acid or ester functionality can be selected from the reagent known in the art for the same purpose and preferably can be selected from chiral or achiral amine of general formula, R_a'R_b'R_c'CNH₂

wherein R_a ; R'y and R_c- can be same or different and are as defined above

Specifically, present invention provides a process for preparation of acid intermediate of formula Ila by resolution of racemic form of compound of formula of lib.

Generally, process of resolution involves formation of diastereomeric salt of racemic compound of formula lib in a suitable solvent using a suitable resolving agent, preferably optically active amine. The resolving agent used for resolution of compound of formula lib can be selected from the reagent known and preferably can be selected from chiral or achiral amine of general formula, R_a'R_b'R_C'CNH₂ wherein R_a-, R and Rc- are as defined above. Resolving agent can be selected depending upon the desired isomer and preferably can be selected from arylmethyl amine, benzylamine; a-napthylethyl amine, β-napthylethyl amine, a-methylbenzylamine, a-alkylbenzylamine, a-ethylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, brucine, sn chinine, 1 -amino tetralin, 1 -amino indane, and the like can be employed for the resolution. The specific isomer of the resolving agent [whether (R) or (S)] used for resolution depends on the isomer which needs to be prepared. Solvent employed for resolution is not critical, thus suitable solvent can be selected on the basis whether diastereomeric salt precipitates out differently. Preferably solvent includes but not limited to protic solvents such as water, C_MO alcohols like methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tertiary butanol; C4-i₀ ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4 dioxane, 1,2 dimethoxy ethane, diphenyl ether; halogenated solvents such as chloroform or dichloromethane; straight chain , branched or cyclic or aliphatic (C_5-i₀) or aromatic (C_5-i₀) hydrocarbon solvents such as pentane, n-hexane, cyclo-hexane, n-heptane, toluene, ortho xylene , meta xylene, para xylene, ethyl benzene; nitriles such as acetonitrile, propionitrile; C_2-g esters such as ethyl acetate, methyl acetate, isopropyl acetate; C_3-8 ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; and the like or mixture thereof. Usually reaction is carried out at a temperature of -20 °C to boiling point of the solvent for few minutes to few hours, preferably at a temperature of 0 °C to boiling point of the solvent for 24 hours, more preferably till the completion of salt formation. The reaction is thereafter cooled to ambient temperature for a time sufficient to ensure the complete precipitation of the desired salt. The salt of desired isomer i.e. (R),(R) can be isolated from the reaction mixture by employing suitable techniques such as filtration or centrifugation.

In another alternate way, the resolution process can be carried out using achiral amine followed by chiral amine.

Similarly, other isomers such as (S)(S), (S)(R) or (R)(S) can be prepared by the resolution of racemic intermediate of formula lib using a suitable isomer of resolving agent. Alternatively, other isomer can also be prepared from the filtrate obtained during the resolution of racemic intermediate of formula lib to give salt of (R)(R)-isomer i.e. intermediate of formula Ila.

The salt thus prepared can be optionally crystallized with a suitable solvent to enhance the enantiomeric purity of the product. Suitable solvent includes but not limited to such as protic solvents such as water, CM_O alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tertiary butanol; Gno ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4 dioxane, 1,2 dimethoxy ethane, diphenyl ether, halogenated solvents such as chloroform or dichloromethane; straight chain , branched or cyclic or aliphatic (Cs-io) or aromatic (C_5-10) hydrocarbon solvents such as pentane, n-hexane, cyclo-hexane, n-heptane, toluene, ortho xylene , meta xylene, para xylene, ethyl benzene; nitriles such as acetonitrile, propionitrile; C_2-8 esters such as ethyl acetate, methyl acetate, isopropyl acetate; C_3-8 ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; and the like or mixture thereof. Specifically, salt in a suitable solvent is heated to a temperature of 20 °C to reflux temperature of the solvent for 3 to 4 hours, preferably till clear solution obtained. Precipitation of the salt can be initiated by reducing the temperature of the resulting solution or by adding an antisolvent to same. Salt thus precipitated can be isolated from the reaction mixture by employing suitable techniques such as filtration or centrifugation. Re-crystallizations of the salt can be optionally repeated until a product of desired chiral purity is obtained and/or desired as well as optical rotatory power.

Intermediate of formula Ha or other isomer can be recovered from the corresponding diastereomeric salt by its neutralization using a suitable acid.

Generally, neutraUzation process involves treatment of diastereomeric salt in solvent with a suitable acid at a temperature of 0 °C to 40 °C for 15 minutes to 3 hours. Preferably, reaction is carried out till complete neutralization. Acid employed for the neutralization includes organic acid such as R₃COOH, R₃S0₃H (wherein R₃ is as defined above); or inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or nitric acid. After completion of reaction, layers were separated. Acid intermediate of formula Ha can be isolated from the resulting organic layer by the removal of solvent using suitable techniques such as evaporation or distillation and the like.

Racemic hydroxyl intermediate of formula IV of the present invention can be resolved by converting hydroxy functionality to respective ester or ester-acid or ester-amine derivatives.

l-Phenyl-3-dimethylaminopropane derivatives of formula I including its isomers, diastereomers, enantiomers, racemates can be converted in a known manner into their salts with physiologically acceptable acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. Salt formation is preferably effected in a solvent that includes water, ether such as diethyl ether, diisopropyl ether; ester such as alkyl acetates or propionates; ketone such as acetone and/or 2-butanone, methyl iso-butyl ketone; alcohol, aliphatic or aromatic hydrocarbon; halogenated solvents, nitriles; or aprotic solvent and the like or mixture thereof. The weak salts thus prepared can be converted to hydrochloride salt by the methods known in the art or by using gaseous hydrogen chloride, or solvent trapped hydrogen chloride; aqueous hydrochloric acid; other chloride ion providing reagent such as trimethylsilyl chloride (TMSC1).H₂0, ammonium chloride, thionyl chloride, sulfuryl chloride, phosphorus oxy chloride, phosphorus pentachloride, phosphoms trichloride, (RaRbRc)N.HCl, RaCOX; wherein Ra, Rt» Rc are as defined above and X represent halide such as chloro, bromo.fluoro and the like. Preferably tapentadol hydrochloride is prepared.

According to another embodiment, present invention provides process for the preparation of intermediate of formula II or its isomers, enantiomers, diastereomers, racemates, solvates, hydrates or pharmaceutically acceptable salts thereof from compound of formula DC, through optional isolation of corresponding amide intermediate.

Generally, process involves the synthesis of intermediate of formula II by. hydrolyzing the cyano intermediate of formula EX. The reaction can be carried out in single step or in multistep by mamtaining the suitable reaction condition such as amount of the reagent, temperature, reaction time as well as nature of reagent employed for the reaction. The reagent employed for the reaction can be selected from any reagent known in the art that can effectively hydrolyze cyano group provided they have no effect on other functionalities of the molecule. Specifically, the hydrolysis of the cyanide group can be carried out under acidic or basic conditions. Acid employed for the reaction includes inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; or organic acid such as alkyl or aryl carboxylic acid, alkyl or aryl sulfonic acid and the like. Base employed for the reaction includes inorganic base selected from alkali or alkaline metal hydroxide such as sodium hydroxide, potassium hydroxide, hthium hydroxide and the like (with or without additives). Usually the reaction can be carried out at a temperature of -30 to 150°C, till the completion of the reaction but temperature and other reaction condition can vary depending upon the nature of the intermediate of formula IX. The solvent employed for the reaction includes water; halogenated solvents such as dichloromethane, chloroform, esters such as ethyl acetate, methyl acetate, isopropyl acetate; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4 dioxane, 1,2 dimethoxy ethane, diphenyl ether; aliphatic or aromatic hydrocarbon such as pentane, n-hexane, cyclo-hexane, n-heptane, toluene, ortho xylene , meta xylene, para xylene, ethyl benzene; nitriles such as acetonitrile, propionitrile; aprotic solvents such as dimethylsulfoxide; alcohols, glycols and the like or mixture thereof. Alternatively, intermediate of formula II can be prepared from the cyano intermediate of formula IX by optionally isolating corresponding amide intermediate. The compound of formula II, thus formed can be isolated from the reaction mixture by the suitable methods known in the art or can be proceeded as such for the further reaction. Specifically, after the completion of the reaction, reaction mixture was diluted with water followed by washing with a suitable organic solvent, which includes ethers such as isopropyl ether, methyl tertiary butyl ether; aliphatic or aromatic hydrogen such as toluene; ester such ethyl acetate and the like. The resulting aqueous layer is then acidified using a suitable organic or inorganic acid and then extracted with a suitable solvent as described above. The desired compound can be recovered from the resulting solution by the techniques known in the art for the removal of solvent such as distillation and the like. The isolated acid intermediate of formula II can optionally be purified to enhance the purity and/or to remove the undesired impurities present in the product by the methods known in the art. Preferably, compound of formula lie can be isolated from the reaction mixture.

According to another embodiment, present invention provides a process for the preparation of acid intermediate of formula Π starting from intermediate of formula X using a suitable reagent depending upon substituents of compound of formula X.

In a preferred embodiment, compound of formula II can be prepared starting from the compound of formula X (wherein both R7 and R_$ are -CN ) which has structure of formula Xa by employing hydrolysis and decarboxylation.

Generally, process involves reacting dicyano compound of formula Xa with a suitable hydrolyzing reagent. The reaction can be carried out in single step or in multistep by maintaining the suitable reaction condition such as amount of the reagent, temperature, reaction time as well as nature of reagent employed for the reaction and by the optional isolation of one or more corresponding intermediates having general formula XI.. The hydrolyzing reagent employed for the reaction can be selected from any reagent known in the art that can effectively hydrolyze cyano group to acid or amide group provided they have no effect on other functionalities of the molecule. Specifically, the reaction can be carried out under acidic or basic conditions. Acid or base, solvent and other reaction conditions employed for the hydrolysis is same as described above. After the completion of hydrolysis reaction, resulting product is then decarboxylated to give intermediate of formula II. Decarboxylation reaction can be performed in the presence of suitable solvent with or without catalyst under inert reaction conditions. The suitable solvent used for the decarboxylation can be selected from water, quinoline, dimethylsulphoxide, dimethylformamide, dimethylacetamide, diphenylether, dimethyl aniline, pyridine, halogenated solvents such as dichloromethane, chloroform, esters such as ethyl acetate, methyl acetate, isopropyl acetate; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, cyclopentyl methyl ether, tetrahydrofuran, "2-methyl tetrahydrofuran, 1,4 dioxane, 1,2 dimethoxy ethane, diphenyl ether; aliphatic or aromatic hydrocarbon such as pentane, n-hexane, cyclo-hexane, n-heptane, toluene, ortho xylene , meta xylene, para xylene, ethyl benzene; nitriles such as acetonitrile, propionitrile; alcohols and the like. The reaction can be employed in the presence of transition metal catalyst such as copper oxides, copper chromite, copper, alkali metal halide such as lithium chloride, sodium chloride and its salts or a suitable base selected from alkali or alkaline metal carbonates, bicarbonates, hydroxides, alkoxides, hydride thereof or combination thereof. Usually the reaction can be carried out at a temperature of -30 to 250°C, till the completion of the reaction but temperature and other reaction condition can vary depending upon the nature of the intermediate of formula II. Intermediate of formula II can be prepared simultaneously hydrolysis and decarboxylation of intermediate of formula Xa.

Preferably, intermediate of formula lie can be prepared from the dicyano compound of formula Xa by using a suitable hydrolyzing and decarboxylating reagent as described above.

The compound of formula Π, thus formed can be isolated from the reaction mixture by the suitable methods known in the art or can be proceeded as such for the further reaction.

In another preferred embodiment, compound of formula Π can be prepared starting from the compound of formula X (wherein one of R₇ and R_# is -CNand other is -COOR₉) which has structure of formula Xb. Generally, process involves reaction of cyano ester compound of formula Xb with a suitable hydrolyzing and decarboxylating reagent. The reagent employed for the reaction can be selected from any reagent known in the art that can effectively served the purpose provided they have no effect on other functionalities of the molecule. Hydrolyzing reagent, decarboxylating reagent, solvent and other reaction conditions are same as defined above.

Alternatively, intermediate of formula Π can be prepared from the cyano ester compound of formula Xb by optionally isolating corresponding amide intermediate. The reaction can be carried out in single step or in multistep by maintaining the suitable reaction condition such as amount of the reagent, temperature, reaction time as well as nature of reagent employed for the reaction and by the optional isolation of corresponding amide intermediate. The compound of formula Π, thus formed can be isolated from the reaction mixture by the suitable methods known in the art or as described earlier in the present invention. Compound of formula Π can be used in situ for the further reaction. Preferably, the compound of formula He can be isolated from the reaction using suitable reaction condition.

In yet another preferred embodiment, compound of formula Π can be prepared starting from the compound of formula X (wherein R₇ and Rs are selected from -COOR9, -COOR9 ') which has structure of formula Xc. Generally, process involves reaction of compound of formula Xc using a suitable decarboxylating agent and hydrolysis. Decarboxylation reaction can be performed in the presence of suitable solvent with or without catalyst under inert reaction conditions. Solvent, catalyst and other reaction conditions for the decarboxylation reaction are same as described above. The hydrolysis can be carried out under acidic or basic conditions. Acid or base and other reaction conditions employed for the hydrolysis reaction are same as described above. The reaction is preferably conducted at a temperature of about 0 °C to 250°C, preferably till reaction completion. In yet another preferred embodiment, compound of formula II can be prepared starting from the compound of formula X (wherein one of R7 and Rs are selected from— CONR₂R₂ ' and other is -CN) which has structure of formula Xd.

Generally, process involves reaction of compound of formula Xd using a suitable hydrolysis and decarboxylating reagent. Reagent employed for the deacrboxylation and hydrolysis reaction are same as described above. The reaction can be carried out to give directly compound of formula II using suitable condition or multi step by isolating the corresponding diamide, acid amide intermediates and other possible intermediates by mamtaining the reaction conditions, amount of reagent, and solvent employed. The compound of formula II, thus formed can be isolated from the reaction mixture by the suitable methods known in the art or can be proceeded as such for the further reaction. Preferably, the compound of formula lie can be isolated from the reaction mixture.

In still another preferred embodiment, compound of formula Π can be prepared starting from the compound of formula X (wherein one ofR and Rg are selected from -COSR₉ and other is -CN) which has structure of formula Xe.

Generally, process involves reacting the compound of formula Xe using a suitable hydrolyzing and decarboxylating reagent to form compound of formula Π. Hydrolyzing reagent, decarboxylating reagent, solvent and other reaction conditions are same as described above.

Similarly, compound of formula X with other substituents can be converted to desired intermediate of formula Π using suitable reagent known in the art and can be selected depending upon the nature of the substituents.

The isolated intermediate of formula Π prepared by any of the methods as described by the present invention can optionally be purified to enhance the purity and/or to remove undesired impurities present in the product by methods known in the art.

If, the intermediate of formula II prepared by the above described process is acid intermediate of formula He (a variant of compound of formula Π, wherein R ' is hydrogen),whic can be converted to corresponding ester intermediate using a suitable esterifying agent, that can be further proceeded for the further reaction.. Generally, the process involves the esterification of compound of formula Π (wherein R ' is hydrogen) using a suitable esterifying agent at a temperature of -20 to 150 °C, for few minutes to few hours, preferably till the completion of the reaction. Esterifying reaction can be carried out using a suitable alcohol of general formula R'OH wherein R ' is as defined above in the presence of a suitable catalyst selected from Lewis acid such as borane trifluoride; diethyl ether complex; boric acid and the like; or acids such as carboxylic acids, sulfonic acids, phosphoric acid, sulfuric acid or derivative thereof and the like. The esterification reaction can be carried by activating the acid compound of formula lie using a suitable reagent selected from acetic anhydride, thionyl chloride, boric acid and other reagents known in the art that can activate an acid functionality. The activated acid compound can be then made to react with suitable alcohol of general formula R'OH- wherein R' is as defined above in the presence of suitable base. Base used for the reaction can be organic or inorganic base. Organic base can be trialkyl amine such as triethyl amine and the like. Inorganic base can be alkali or alkali metal hydride, alkoxide, hydride, carbonate, bicarbonate thereof such as sodium bicarbonate and the like.

If, the intermediate of formula Π prepared by the above described process is ester intermediate of formula lid (a variant of compound of formula II),

Formula Ud

wherein R_/ and R ' areas defined above; provided R ' is not hydrogen

can be hydrolyzed to corresponding acid intermediate of formula lie that can be further proceeded for the further reaction.

Generally, process involves hydrolysis of compound of formula Ed (wherein R' is as defined above provided R ' is not hydrogen) using a suitable hydrolyzing agent in a suitable solvent at a temperature of - 10°C to 180°C. Suitable hydrolyzing agent can be selected from the reagent known in the art that can serve the purpose or preferably can be carried out in the presence of a suitable acid or base. Acid employed in the reaction can be inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like. Organic acids include carboxylic acid such as aliphatic or aromatic carboxylic acid and the like or combination thereof. Base employed for the hydrolysis can be organic or inorganic base. Organic base includes amine such as substituted amine and the like; inorganic base includes alkali or alkaline metal hydroxide, alkoxide, hydride, carbonate or bicarbonate thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like. Solvents for carrying hydrolysis include water, aliphatic or aromatic hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane, chloroform, esters such as ethyl acetate, methyl acetate, isopropyl acetate; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4 dioxane, 1,2 dimethoxy ethane, diphenyl ether, aliphatic or aromatic hydrocarbon such as pentane, n- hexane, cyclo-hexane, n-heptane, toluene, ortho xylene , meta xylene, para xylene, ethyl benzene; nitriles such as acetonitrile, propionitrile; aprotic solvents such as dimethylformamide, dimethylsulfoxide, N- methylpyrrolidinone; alcohol and the like or mixture thereof. The acid intermediate of formula lie can be isolated from the reaction mixture or reaction mixture can be used as such for the next stage of the reaction. Before proceeding to next step, the acid intermediate of formula lie can optionally be purified to minimize the presence of impurities as well as to increase purity of the desired intermediate.

The other starting compound as described in the present invention can be prepared by the methods known in the art or by the process described in our co-pending application.

The order and manner of combining the reactants at any stage of the process are not important and may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further, any of the reactants may be dissolved together as sub-groups, and those solutions may be combined in any order. The time required for the completion of the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. Wherever required, progress of the reaction may be monitored by suitable chromatographic techniques such as High performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

Thus, isolated final product i.e. l-phenyl-3-dimemylaminopropane derivatives of formula I as well as intermediates described here in the present invention may be optionally purified to enhance the purity of the product. Any suitable purification procedure such as, for example, crystallization, derivatisation, slurry wash, salt preparation, various chromatographic techniques, solvent anti-solvent system or combination of these procedures, may be employed to get the purified material. However, other equivalent procedures such as acid-base treatment or acid-acid treatment could, also be used, to purify the intermediates as well as final product. The solvents used for the purification of final compound and intermediates of the present invention may be selected depending upon the nature of the compound to be purified, however the solvent can be chosen amongst water, Ci^ alcohols, aliphatic C3-6 ketones, aliphatic or aromatic hydrocarbons, aliphatic esters, C_3-6 ethers, nitrile, a halogenated solvents, aprotic solvents such as N,N- dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrroUdinone, sulfolane and the like or mixtures thereof in suitable proportion.

As used herein the term "conventional methods for the isolation of intermediates as well as final product" may be varied depending upon the nature of the reactions, nature product of the reaction, medium of the reaction and the like, the suitable conventional methods can be selected amongst but not limited to distillation of the solvent, addition of water to the reaction mixture followed by extraction with water immiscible solvents, removal of the insoluble particles from the reaction mixture, if present, by filtration or centrifugation or by decantation, addition of water immiscible organic solvent, addition of a solvent to the reaction mixture which precipitate the product, neutralizing the reaction mixture with a suitable acid or base whichever is applicable.

The major advantage of the present invention is to provide an efficient and industrially advantageous process for preparation of l-phenyl-3-dimeAylaminopropane derivatives of formula I, preferably tapentadol. Present invention also provides an efficient process for preparation of tapentadol or pharmaceutically acceptable salts of high enantiomeric purity. Further, the present invention also provides novel intermediates, which are useful in the preparation of the tapentadol and its pharmaceutically salts thereof.

Although, following examples illustrate practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.

Example 1: Preparation of l-(3-methoxy-phenyl)-propan-l-ol

To a stirred solution of m-anisaldehyde (30 g, 0.220 mol) in tetrahydrofiiran (150 ml) at -5 °C under inert atmosphere, ethyl magnesium bromide (180 ml, 0.540mol) was added and stirred for 2 hours. Reaction mixture was quenched with 20% aqueous citric acid (800 ml) at 0°C followed by layer separation. Tetrahydrofuran layer was separated and tetrahydrofuran distilled off to get a residue. The aqueous layer was extracted with isopropyl ether (300ml). Residue obtained after distillation of tetrahydrofuran and extract of isopropyl ether were combined, washed with demineralised water (2 x 50ml), dried over sodium sulphate and distilled to give 34.8 g (95%) of the title compound.

Ή-NMR (CDC1₃): 7.0-(4H,m,ArH); 4.48-(lH,t,CHAr); 3.75-(3H, s, OCH₃); 1.74-(2H,m,CH₃CH₂); 0.88- (3H,t,CH₃CH₂);

Example 2: Preparation of l-(l-bromo-propyl)-3-methoxy-benzene

Phosphorus tribromide (41.25g, 0.152 mol) was added to l-(3-methoxy-phenyl)-propan-l-ol (23 g, 0.138 mol) at 0°C and reaction mixture was stirred at 25°C for 2 hours. Ice (230 g) was added to the reaction mixture at 0 °C and product thus formed was extracted with isopropyl ether (3 x 50ml). Extracts were combined and washed with demineralized water (2 x 30ml). The resulting organic layer was dried over sodium sulphate and distilled to give 30g (94.7%) of the title compound.

'H-NMR (CDCI₃): 7.0-(4H, m, ArH); 4.83-(lH, m,CHAr); 3.80-(3H, s ,OCH₃); 2.19 (2H, m, CH₂CH₃);0.99-(3H,t,CH₃CH₂)

Example 3: Preparation of l-(l-chloro-propyl)-3-methoxy-benzene

Method A: To a solution of l-(3-methoxy-phenyl)-propan-l-ol (0.2 g, 0.001 mol) in dichloromethane (2 ml) and dimethylformarnide (0.17 g), thionyl chloride (0.18 g, 0.001 mol) was added at 25 °C and stirred for 2 hours. Ice (2g) was added to the reaction mixture at 0 °C and product thus formed was extracted with isopropyl ether (3 x 3ml). Extracts were combined and organic layer was washed with demineralised water (2 x 1ml). The resulting organic layer was dried over sodium sulphate and distilled to give 0.21 g (95%) of the title compound.

Method B: Preparation of l-(l-chloro-propyl)-3-methoxy-beiizene

To a solution of l-(3-methoxy-phenyl)-propan-l-ol (0.2 g, 0.001 mol) in dichloromethane (2ml) and dimethylformamide (0.17g), phosphorus oxychloride (0.55 g, 0.003 mol) was added and reaction mixture was stirred at 40°C for 2 hours. Ice (2 g) was added at 0°C to the reaction mixture and product thus formed was extracted with isopropyl ether (3 x 3ml). Extracts were combined and organic layer was washed with demineralised water (2 x 1ml). The resulting organic layer was dried over sodium sulphate and distilled to give 0.19 g (86 %) ofthe title compound.

Example 4: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid

Step I: Preparation of 2-[l-(3-methoxy-phenyl)-propyl]-2-methyl-malonic acid diethyl ester

A suspension of dimethylsulfoxide (50 ml) and sodium hydride (5.52 g, 0.114 mol) was stirred at 60°C for

1 hour and then cooled to ambient temperature. 2- ethyl-rnalonic acid diethyl ester (10 g, 0.057 mol) was added to the reaction mixture and was stirred for 1 hour at 25°C. Thereafter, l-(l-bromo-propyl)-3- methoxy-benzene (13.2 g, 0.057 mol) was added to the reaction mixture and stirred for 5 hours. After the completion of the reaction (monitored by TLC), demineralised water (100 ml) was added to the reaction mixture followed by extraction with isopropyl ether (2 x 50ml). Organic layer was washed with demineralised water, dried over sodium sulphate and distilled to give 14.78 g (79.8%) of the title compound.

Step Π: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid

To a stirred solution of 2-[l-(3-methoxy-phenyl)-propyl]-2-methyl-malonic acid diethyl ester (lg, 0.003 mol) in monoethylene glycol (5 ml), sodium hydroxide (0.5g, 0.012 mol) was added and reaction mixture was heated to 170-180°C for 4 hours. After the completion of the reaction (monitored by TLC), demineralised water (10ml) was added to the reaction mixture at 50°C. The resulting reaction mixture was washed with isopropyl ether (2 x 5ml). Organic layer was discarded and concentrated hydrochloric acid was added to the aqueous layer to adjust pH to 1. The resulting product was extracted by isopropyl ether (3 x 5ml) and organic layer was washed with demineralised water. The resulting organic layer was dried over sodium sulphate and distilled to give 0.94 g (93%) of the title compound.

Example 5: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid

Step I: Preparation of 2-cyano-3-(3-methoxy-phenyl)-pentanoic acid ethyl ester

To a solution of ethyl cyanoacetate (O.lg, 0.001 mol) and 1,8-diazabicyclo [5.4.0]undec-7-ene (0.13g, 0.001 mol), l-(l-bromo-propyl)-3-methoxy-benzene (0.2 g, 0.001 mol) was added and stirred at 25°C for 3 hours. Demineralised water (0.6ml) was added to reaction mixture followed by extraction with isopropyl ether (2 x 3ml). Organic layer was washed with demineralised water, dried over sodium sulphate and solvents were distilled to give 0.22 g (95%) of the title compound.

Step Π: Preparation of 2-cyano-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid ethyl ester

Method A: To a solution of 2-cyano-3-(3-methoxy-phenyl)-pentanoic acid ethyl ester (322gm, 1.23 mol) in dimethylsulfoxide (966ml), potassium carbonate (68 lg, 4.92 mol) was added and stirred for 15 minutes at 25°C. Thereafter, methyl iodide (525 g, 3.69 mol) was added to the reaction mixture and stirred for 1 hour at 25°C. Water (2.9 L) was added to the reaction mixture and reaction mixture was extracted with isopropyl ether (3 x 500 ml). Combined organic layers were washed with demineralised water, dried over sodium sulphate and distilled to give 337 g (99.4%) of the title compound.

Method B: To a solution of 2-cyano-3-(3-methoxy-phenyl)-pentanoic acid ethyl ester (1 g, 0.004 mol) in dimethylsulfoxide (5 ml), potassium carbonate (2.12 g, 0.016 mol) was added and stirred for 15 minutes at 25°C. Thereafter, dimethyl sulphate (1 g, 0.008 mol) was added to the reaction mixture and stirred for 15 hours at 25°C. Water (15 ml) was added to the reaction and then reaction mixture was extracted with isopropyl ether (3 x 10ml). Combined organic layers were washed with demineralised water, dried over sodium sulphate and distilled to give 1 g (95 %) of the title compound

'H-NMR CDCb): 7.10 (4H,m,ArH); 4.32,3.95 (2H,q, each, OCH₂CH₃ both diast); 3.82,3.80 (3H, s each, OCH₃ both diast); 2.96,2.82 (lH,dd each, CHAr both diast.); 2.0 (2H,m, CH₃CH₂-C of both diast.); 1.7,1.32 (3H, s, CH₃-C-CN of both diast.); 1.38,0.98 (3H, t, each, CH₃CH₂0 of both diast); 0.8, 0.78 (3H,t,each, CH₃CH₂-C of both diast.)

Step III: Preparation of 3-(3-methoxy-phenyl)-2-niethyl-pentanoic acid

To a stirred solution of 2-cyano-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid ethyl ester (lOg, 0.036 mol) in monoethylene glycol (40 ml), sodium hydroxide (7.72 g, 0.216 mol) was added and heated to 170- 180 °C for 4 hours. Water was added (120 ml) to the reaction mixture at 50°C. The resulting reaction mixture was washed with isopropyl ether (2 x 50ml) and organic layer was discarded. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 1. The product thus formed was extracted with isopropyl ether (3 x 5ml). Organic layer was washed with demineralised water, dried over sodium sulphate and distilled to give 4.3 g (54 %) of the title compound.

Example 6: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid

Step I: Preparation of 2-(3-methoxy-benzylidene)-niaIononitrile

l,8-Diazabicyclo[5.4.0]undec-7-ene (1.1 lg, 0.007 mol) was added to a stirred mixture of meta- anisaldehyde (lOgm, 0.073 mol) and malononitrile (5.34 g, 0.080 mol) and was stirred for 6 hours at 50- 60°C. Thereafter, reaction mixture was cooled to room temperature. Dichloromethane (50 ml) and water (20 ml) was added to the reaction mixture and stirred for 15 minutes followed by layers separation. The organic layer was washed with water (2 x 10ml), 10 % sodium hydrogen carbonate (1 x 10ml) and water (1 x 20ml) subsequently. The resulting organic layer was dried over anhydrous sodium sulfate, distilled to give 16g of the title compound.

Step Π: Preparation of 2-[l-(3-methoxy-phenyl)-propyl]-malononitrile

To a stirred mixture of 2-(3-methoxy-benzylidene)-malononitrile (15 g, 0.081 mol) in dry tetrahydrofuran (60 ml) under nitrogen at -10° to -15°C, a solution of ethyl magnesium bromide ( 54 ml, 0.162 mol) in tetrahydrofiiran was added and stirred for 1 hour. Reaction mixture was further stirred at 15-25 °C till completion of reaction (monitored by TLC). After the completion of the reaction, reaction mixture was quenched with saturated aqueous ammonium chloride (50 ml) at 0 to 5°C and extracted with isopropyl ether (3 x 50ml). The organic layers were combined and washed with water (50 ml). The resulting organic layer was dried over anhydrous sodium sulfate and distilled off to give 16 g of title compound.

!H-NMR (CDC1₃): 7.1 (4H, m, ArH); 3.87 (1H, d, CHCN); 3.82 (3H, s, OCH₃); 3.07(1H, m, CHAr); 2.03(2H, m, CH₃CH₂); 0.91 (3H,t,CH₃CH₂)

Step ΙΠ: Preparation of 2-[l-(3-methoxy-phenyl)-propyl]-2-methyl-nialononitrile

To a solution of 2-[l-(3-methoxy-phenyl)-propyl]-malononitrile (15 g, 0.07 mol) in dimethylsulfoxide (75 ml), potassium carbonate (38.75 g, 0.28 mol) was added and stirred for 15 minutes at 25°C. Thereafter, methyl iodide (30 g, 0.21 mol) was added to the reaction mixture and stirred for 1 hour at 25°C followed by addition of water (150ml). Reaction mixture was extracted with methyl tertiary butyl ether (2 x 75ml) and the combined organic layers were washed with demineralised water. The resulting organic layer was dried over sodium sulphate and distilled to give 16 g of the title compound.

^-NMR (CDCI₃): 7.1 (4H,m,ArH); 3.81 (3H, s, OCH₃); 2.81 (1H, m, CHAr); 2.13 (2H, m, CH₃CH₂); 1.59 (3H, s, CH₃CCN); 0.84 (3H, t, CH₃CH₂);

Step IV: Preparation of 3-(3-methoxy-phenyl)-2-niethyl-pentanoic acid

To a stirred solution of 2-[l-(3-methoxy-phenyl)-propyl]-2-methyl-malononitrile (0.5 g, 0.002 mol) in monoethylene glycol (2.5 ml), sodium hydroxide (0.35 g, 0.196 mol) and heated to 170-180 °C for 4 hours. After the completion of the reaction, water was added (2 ml) to the reaction mixture at 50 °C and washed with isopropyl ether (2 x 5ml). Organic layer was discarded and concentrated hydrochloric acid was added to the aqueous layer to adjust pH to 1. The thus formed product was extracted with isopropyl ether (3 x 5ml). Organic layer was washed with demineralised water, dried over sodium sulphate and distilled to give 0.4 g (82 %) of the title compound. Example 7: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid

To a stirred solution 3-(3-methoxy-phenyl)-2-methyl-pentanenitrile (lOg, 0.049 mol) in monoethylene glycol (40ml), sodium hydroxide powder (11.8g, 0.295 mol) was added and heated to 170-180 °C for 4 hours. Water was added (120 ml) to the reaction mixture at 50 °C and washed with isopropyl ether (2 x 50 ml). Organic layer was discarded and concentrated hydrochloric acid was added to the aqueous layer adjusting pH of the reaction mixture to 1. The resulting product was extracted using methyl tertiary butyl ether (3 x 50ml) and organic layer was washed with dernineralized water. The resulting organic layer was dried over sodium sulphate and distilled to give 10.2 g (92.9%) of the title compound .

Example 8: Preparation of 3-(3-methoxy-phenyl)-2-methyI-pentanoic acid

To a stirred solution of 2-cyano-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid dimethylamide (0.5 g, 0.002 mol) in monoethylene glycol (2.5 ml), sodium hydroxide powder (0.29 g, 0.007 mol) was added at ambient temperature and heated to 170-180 °C for 4 hours. Water was added (2 ml) to the reaction mixture at 50 °C and the reaction mixture was washed with isopropyl ether (2 x 5 ml). Layers were separated and concentrated hydrochloric acid was added to the aqueous layer till pH 1. Resulting product was extracted with isopropyl ether (3 x 5ml) from the reaction mixture. Organic layer was washed with demineralised water, dried over sodium sulphate and distilled to give 0.31 g of the title compound.

Example 9: Preparation of 3-(3-methoxy-phenyl)-2-methyI-pentanoic acid

To a stirred solution of 2-cyano-3-(3-methoxy-phenyl)-2-methyl-pentanethioic acid S-phenyl ester (1 g, 0.003 mol) in monoethylene glycol (5ml, sodium hydroxide powder (0.29 g, 0.007 mol) was added at ambient temperature and heated to 170-180 °C for 4 hours. Water was added (10 ml) at 50 °C and the reaction mixture washed with isopropyl ether (2 5 ml). Layers were separated and concentrated hydrochloric acid was added to the aqueous layer till pH 1. Resulting product was extracted with isopropyl ether (3 x 5ml) from the reaction mixture. Organic layer was washed with demineralised water, dried over sodium sulphate and distilled to give 0.465 g of the title compound.

Compounds prepared in example 4 to 9 displays the same Ή-NMR (CDC1₃): 7.0-(4H,rn,ArH); 3.81,3.80-(3H, s each, OC¾ of both diast.); 2.7-(2H, m,CHAr & CHCOOH of both dias ); 1.75,1.77- (3H,t,each, CH₃CH₂ of both diast.); 1.7 - (2H, m,CH₂CH₃ of both diast); 0.95,1.23-(3H, d, each, CH₃CH of both diast.);

Example 10: Preparation of 3-(3-methoxy-phenyl)-2-metliyl-pentan-l-ol

Method A: To a stirred solution of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (8 g, 0.036 mol) in dry tetrahydrofuran (40ml) under nitrogen atmosphere, borane-dimethylsulfide (4.1g, 0.041 mol) was added at 20-25 °C and stirred at 50-55° C for 1 hour. Methanol (10 ml) was added to the reaction mixture at 0-5°C, stirred for 30 minutes. Solvents were distilled off and resulting residue was dissolved in isopropyl ether (50ml. The mixture was washed with 5% aqueous hydrochloric acid (20ml) and water (20 ml). Isopropyl ether layer was dried over sodium sulphate and distilled off to give 6.2 g (82.7%) of the title compound. Method B: To a stirred solution of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (7.5g, 0.034 mol) in dry tetrahydrofuran (38 ml) under nitrogen atmosphere, borane-dimethylsulfide (3.85g, 0.039 mol) was added at 20-25°C. The reaction mass was stirred at 50-55°C for 1 hour and methanol was added to the reaction mixture at 0-5°C. The reaction mixture was stirred for 30 minutes and solvents were distilled off. The residue thus obtained was dissolved in isopropyl ether (50ml) and washed with 5% aqueous hydrochloric acid (20 ml) and water (20 ml). Organic layer was dried over sodium sulphate and distilled off to give 6.9 g (98 %) of the title compound.

Method C:

Step I: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentanal

A stirred solution of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid methyl ester (2.36 g, 0.01 mol) in dichloromethane (12 ml) was cooled to -78 °C and dnsobutylaluminium hydride in tetrahydrofuran (12 ml, 0.012 mol) was added to the mixture. The resulting mixture was stirred at -78 °C for 1 hour and quenched with methanol (0.5 ml) and brine (5 ml). The reaction mixture was warmed to ambient temperature and organic layer was separated, dried, and concentrated to give 1.37 g of title compound.

Step Π: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentan-l-ol

To a solution of 3-(3-methoxy-phenyl)-2-methyl-pentanal (1.03 g, 0.005 mol) in methanol (7 ml) at 10-15 °C, sodium borohydride (0.38 g, 0.01 mol) was added at ambient temperature and stirred for 3 hours. Methanol was distilled off and resulting reaction mixture was added to cold aqueous hydrochloric acid (2 ml). The product was extracted with methyl tert-butyl ether (3 x 7 ml). All organic extracts were combined and washed with water. The organic layer was dried and distilled off to give 0.87 g of title compound.

Example 11: Preparation of toluene-4-sulfonic acid 3-(3-methoxy-phenyl)-2-niethyl-pentyl ester Method A: To a stirred solution of 3-(3-methoxy-phenyl)-2-methyl-pentan-l-ol (0.3 g, 0.001 mol), trietoylarrune (0.174g, 0.002 mol) and

(0.005g, 0.043 mol) in dichloromethane (1.5 ml), p-toluene sulfonyl chloride (0.3g, 0.002 mol) was added to the reaction mixture and was stirred for 6 hours at 25-30°C. Layers were separated and the organic layer was washed with dernineralised water (0.5ml). The resulting organic layer was washed over anhydrous sodium sulphate and distilled off to give 0.3 g of the title compound.

Method B: To a stirred solution of 3-(3-methoxy-phenyl)-2-methyl-pentan-l-ol ( 6.6g, 0.032 mol), triethylamine (4.0g, 0.040 mol), 4^imethylamino pyridine (0.66g, 0.005 mol) in dichloromethane (35 ml), p-toluene sulfanyl chloride (6.94g, 0.036 mol) was added and reaction mixture was stirred for 6 hour at 25- 30°C. Layers were separated and organic layer was washed with dernineralised water (15ml), IN aqueous hydrochloric acid (15ml), again with demineralised water (15ml). The resulting organic layer was dried over anhydrous sodium sulphate and solvent was distilled off to give 10.5 g (91%) of the title compound. Example 12: Preparation of (3-(3-methoxy-phenyl)-2-methyl-pentyl]-dimethyl-amine

Method A: A suspension of N,N-dimethylamine-hydrochloride (0.8 lg, 0.01 mol), sodium hydroxide (0.6 g, 0.015 mol) in dimethylsulfoxide (9ml) at 20-25°C was stirred for 30 minutes. Toluene-4-sulfonic acid 3- (3-methoxy-phenyl)-2-methyl-pentyl ester (1.8 g, 0.005 mol) was then added to the reaction mixture and stirred at 40-45°C for 2 hours. Thereafter, the reaction mixture was quenched with chilled water (18 ml) and extracted with dichloromethane (10 ml). The organic layer was washed water (4ml) and dried over anhydrous sodium sulphate.. The resulting organic layer was distilled off to give 1.2 g (100%) of the title compound.

Method B: A suspension of N^N-^iimemylamine-hydrochloride (4.5g, 0.055 mol) and sodium hydroxide (3.3g, 0.083 mol) in dimethylsulfoxide (50 ml) at 20-25°C was stirred for 10 minutes and toluene-4- sulfonic acid 3-(3-methoxy-phenyl)-2-methyl-pentyl ester (lOg, 0.028 mol) was added to the above mixture. The reaction mixture was stirred at 50-55°C for 2 hours. Thereafter, reaction mixture was quenched with chilled water (150ml) at 15°C and resulting product was extracted with methyl tertiary butyl ether (3 x 50ml). The organic layer was washed with water (40ml x 2), and dried over anhydrous sodium sulfate. The solvent was distilled off to give 6.45 (99%) of the title compound.

Ή- MR (CDCI₃): 6.9 (4H, m, ArH); 3.8 (3H, s, OCH₃); 2.55 (1H, m, CHAr); 2.2 (6H, s, N-CH₃); 2.15 (1H, m, CHCH3); 1.7,1.9 (2H, m, CH₂N); 1.3 (2H, m, CH₃CH₂)

Example 13: Preparation of [3-(3-methoxy-phenyl)-2-methyl-pentyll-dimethyl-amine-hydrochloride

To a stirred solution of [3-(3-memoxy^henyl)-2-memyl-pentyl]Hiimemyl-aniine (0.5 g, 0.002 mol) in isopropyl ether (5 ml), isopropyl ether hydrochloride (1 ml) was added and stirred for 2 hours at 25-30°C. The resulting product was filtered and dried to give 0.45g of the title compound.

Example 14: Preparation of 3-(3-dimethylamino-l-ethyl-2-methyI-propyl)-phenol Method A: A mixture of [3-(3-memoxy-phenyl)-2-memyl-pentyl]-dimemyl-amine (0.5gm, 0.002 mol) and aqueous hydrobromic acid (46%, 10ml) was heated under stirring at 100-105°C for 3 hours and cooled to 20°C. The reaction mixture was basified with potassium carbonate and the resulting product was extracted with methyl tertiary butyl ether (30ml). The organic layer was washed with water (20 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off to give 0.2 g of title compound.

Method B: A mixture of [3-(3-memoxy-phenyl)-2-memyl-pentyl]-dimemyl-amine (0.3g, 0.001 mol), aqueous hydrochloric acid (10 N, 5ml) and sodium bromide (0.03 g) was heated to reflux and stirred for 8 hours. The reaction mixture was cooled to 20 °C. The excess acid of was degassed, and reaction mixture was neutralized with sodium bicarbonate. The resulting product was extracted with dichloromethane (5ml). The organic layer was washed with water (2 ml) and dried over anhydrous sodium sulfate .The solvent was distilled off to give 0.2 g (71%) of the title compound.

Method C: A mixture of [3-(3-memoxy-phenyl)-2-memyl-pentyl]-dimemyl-amine (0.3g, 0.001 mol), aqueous hydrochloric acid (10N, 5ml) and potassium iodide (0.03 g) was heated to reflux and stirred for 8 hours. The reaction mixture was cooled to 20 °C. The excess acid of was degassed, and reaction mixture was neutralized with sodium bicarbonate. The resulting product was extracted with dichloromethane (5ml). The organic layer was washed with water (2 ml) and dried over anhydrous sodium sulfate .The solvent was distilled off to give 0.21 g (74%) of the title compound.

Method D: A mixture of [3-(3-memoxy-phenyl)-2-memyl-pentyl]-dmiemyl-amine (l.Og, 0.004 mol) and aqueous hydrobromic acid (46%, 30ml) was heated under stirring at 100-105 °C for 3 hours and cooled to 20°C. The excess acid of was degassed, and reaction mixture was neutralized with sodium bicarbonate. Resulting product was extracted with dichloromethane (30ml). The organic layer was washed with water (20 ml) and dried over anhydrous sodium sulfate. The resulting organic layer was distilled off to give 0.9 g (96%) of the title compound which was stirred in ethyl acetate (5ml) for 2 hours. The reaction mixture was filtered and dried to give 0.67 g (87 %) of the title compound.

Example 15: Preparation of 3-(3-dimethylamino-l-ethyl-2-methyI-propyl)-phenol hydrochloride To a stirred solution of 3-(3-dimemylaniino-l-ethyl-2-methyl-propyl)-phenol (0.25 g, 0.001 mol) in methanol (2 ml) was added isopropyl ether hydrochloride (0.45 ml, 11.7%) and reaction mixture was stirred for 1 hour at 25-30°C. The solvents were distilled off. The residue thus obtained was stirred in ethyl acetate (3 ml) for 2 hours, filtered and dried to give 0.22 g (76%) of the title compound.

Example 16: Preparation of (R), (R)-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid

Step I: Preparation of (R)-(⁺)-«-niethylbenzylamine salt of (R), (R)-3-(3-methoxy-phenyl)-2-methyI- pentanoic acid

A solution of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (150 g, 0.675 mol) and (R)-(+)-a- memylbenzylamine (41 g, 0.338 mol) in isopropyl ether (825 ml) was stirred at 70-75 °C for 1 hour. Thereafter, reaction mixture was stirred at 20 - 25 °C for 5 hours. Resulting product was filtered, washed with isopropyl ether (150 ml) and dried under vacuum at 40-45 °C to give 40 g of title compound having chiral purity 70.58 %; (S), (S)-isomer of salt: 15.92 %, (R) (S) and (S) (R) isomer of the salt: 13.50 % by HPLC. Resulting crude (R), (R)-isomer (40 g) was purified with acetonitrile to give 19.2 g of the title compound having chiral purity 99.6 % by HPLC.

Step Π: Preparation of (R), (R)-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid

To the above (R), (R)-isomer (19.2 g) in methyl tertiary butyl ether (100 ml); hydrochloric acid (40ml, 3.9%) was added at 20-25 °C and stirred for 30 minutes. Resulting organic layer was separated and washed with water (2 x 30ml). Solvent was distilled off from the organic layer to give 12.7 g of the title compound having chiral purity 99.6 % by HPLC; [a]_D ^RT= - 18.52 (c = 1 %; methanol)

Example 17: Preparation of (R), (R)-3-(3-methoxy-phenyl)-2-inethyl-pentanoic acid

Step I: Preparation of (R)-(+)-a-methylbenzylamine salt of (R), (R)-3-(3-methoxy-phenyl)-2-methyl- pentanoic acid

Benzyl amine (106.09 g) was added to a solution of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (220 g, 0.99 mol) in methyl tert-butyl ether (1.1 L) and refluxed for 30 minutes, cooled to 20-25 °C and stirred for 3 hours. Resulting product was filtered, washed with methyl tert-butyl ether (220 ml). The filtered precipitate was dried under vacuum at 40-45°C to give 146 g of benzyl amine salt of 3-(3-methoxy-phenyl)-2-methyl- pentanoic acid. Methyl tert-butyl ether (530 ml) and hydrochloric acid (500 ml, 3.9%) were added to the resulting salt at 20-25°C and stirred for 30 minutes. Organic layer was separated, washed with water and distilled off to give 96 g of the free acid having chiral purity as (R) (R)-isomer 47.39 %; (S), (S)-isomer 46.51 %; mixture of (R),(S) and (S),(R)-isomer 6.11 % by HPLC.

A solution of the resulting product (96 g,) and (R)-(-)-a-methylbenzylamine (45.8 g) in methyl isobutyl ketone (770ml) was stirred at 70-75 °C to dissolution, cooled to 65°C. The resulting reaction mixture was seeded with (R)-(-)^-memylbenzylamine salt of pure (R),(R) isomer. Reaction mixture was cooled to 20- 25°C and stirred for 12 hours. Solid was filtered, washed with methyl isobutyl ketone (200 ml) and dried under vacuum at 40-45°C to give 125 g of title compound having chiral purity as (R) (R) isomer 61.9 %; (S), (S) isomer36.25%; and other isomer 1.85% by HPLC.

The product thus obtained was crystallized from acetonitrile (900 ml) to give 106 g of product which was further crystallized from acetone (780 ml) to give 55 g of the salt having chiral purity 88 % by HPLC. Resulting product was further crystallized from acetonitrile to give 35 g of the product having chiral purity as (R) (R) isomer 99.3%; (S), (S) isomer 0.7 %; and other isomers were not detected by HPLC.

Step Π: Preparation of (R), (R)-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid

To above prepared salt, methyl tertiary butyl ether (230 ml) and hydrochloric acid

(100ml, 3.9%) were added at 20-25 °C and stirred for 30 minutes. Resulting organic layer was separated and washed with water (2 x 30ml). Solvent was distilled off from organic layer to give 22 g of the title compound having chiral purity 99.7 % by HPLC (SS = 0.23 %); [a]_D ^RT= -18.5 (c = 1%; methanol)

(S)(S)-isomer, (S)(R)-isomer and (R)(S)-isomer of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid were isolated from the filtrate obtained in step I, of example 16 and 17 containing the corresponding isomer.

(S)(S)-isomer, (S)(R)-isomer and (R)(S)-isomer of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid were prepared by the resolution of racemic 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid similar to the method as given in example 16 and 17 using corresponding resolving agent. Above isomers were characterized by analyzing their specific optical resolution as given below:

(S)(S)-isomer shows [a]_D ^RT= +18.1 (c = 1%; toluene);

(S)( R)-isomer shows [a]_D ^RT= + 28 (c = 1%; toluene);

(R)(S)- isomer shows [a]_D ^RT= -29.86 (c = 1 %; toluene).

Example 18: Preparation of (S)(S)- 3-(3-methoxy-phenyl)-2-methyI-pentanoic acid

Step I: Preparation of (S)-(⁺)-«-niethyIbenzylamine salt of (S), (S)-3-(3-methoxy-phenyl)-2-methyl- pentanoic acid

To the filtrate obtained from example 17 step I (after washing with methyl isobutyl ketone), 2N hydrochloric acid (100 ml) was added and stirred. Layers were separated and organic layer was washed with water (2 x 50 ml). Solvent was distilled from the resulting organic layer to give 28 g of product having chiral purity as (S)(S)-isomen 74.22 %, (R)(R)-isomen 9.06 %; other isomers: 16.71% by HPLC.

A solution of resulting product (23 g) and (S)-(-)-a-me&ylberizylamine (6.26 g) in methyl tertiary butyl ether (115 ml) was stirred at 20- 25 °C for 2 hours. The resulting precipitated product was filtered, washed with methyl tertiary butyl ether and dried under vacuum at 40-45 °C to give 16 g of the title compound. The resulting product was crystallized from isopropanol to give title compound having chiral purity of (S)(S)- isomer 99.4 % by HPLC.

Step Π: Preparation of (S), (S)-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid

To above prepared salt, methyl tertiary butyl ether (62 ml) and hydrochloric acid (20 ml, 3.9%) was added at 20-25 °C and stirred for 30 minutes. Resulting organic layer was separated and washed with water. Solvent was distilled off from the organic layer to give 4 g of title compound having chiral purity 99.4 % by HPLC; [a]_D ^RT= +18.0 (c = 1% ; methanol)

Example 19: Preparation of (R), (R)-3-(3-methoxy-phenyl)-2-methyl-pentan-l-ol

Method A: To a stirred solution of (R), (R)-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (5g, 0.022 mol) in dry tetrahydrofuran (25 ml) under nitrogen atmosphere, borane-dimethylsulfide (2.56 ml, 0.025 mol) was added at 20-25 °C and stirred at 50-55° C for 1 hour. Methanol (10 ml) was added to the reaction mixture at 0-5°C, stirred for 30 minutes. Solvents were distilled off and resulting residue was dissolved in isopropyl ether (40ml). The resulting solution was washed with 5% aqueous hydrochloric acid (20 ml) and water (20 ml). Isopropyl ether layer was dried over sodium sulphate and distilled off to give 4.6 g (98%) of the title compound. [a]_D ^RT= 2.76 (c = 1% ; methanol)

Method B:

Step I: Preparation of [R],[R]-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid methyl ester To a stirred solution of (R) (R)-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (7 g, 0.031 mol) in methanol (35 ml) was added concentrated sulfuric acid (3.1 g, 0.031 mol) at 20-25 °C. Reaction mass was stirred at 50-55 °C for 5 hours. The reaction mixture was poured on crushed ice (100 g) and product was extracted by isopropyl ether (3 x 30ml). All organic extracts were combined, washed with water (2 x 30ml), dried over sodium sulphate and distilled off to give 6.69 g (90 %) of title compound.

Step Π: Preparation of (R), (R)-3-(3-methoxy-phenyl)-2-methyI-pentan-l-ol

To a stirred suspension of sodium borohydride (2.1g, 0.056 mol); (R) (R) 3-(3-methoxy-phenyl)-2-methyl- pentanoic acid methyl ester (6.5g, 0.028 mol) in dry tetrahydrofuran (33 ml) at 50-55 °C, methanol (10 ml) was added slowly. Reaction mass was stirred at 50-55 °C for 4 hours and solvents were distilled off to give a residue. The resulting residue was cooled to 0 °C followed by addition of chilled water (50 ml) to the reaction mixture. The product was extracted using dichloromethane (3 x 30ml). All the organic extracts were combined, washed with water (2 x 30ml), dried over sodium sulphate and distilled off to give 4.98 g (87 %) of title compound.

Method C:

Step I: Preparation of (R),(R)-3-(3-niethoxy-phenyl)-2-methyl-pentanoyl chloride

Thionyl chloride (4.5 g, 0.037 mol) was added to a solution of (R),(R)-3-(3-methoxy-phenyl)-2-methyl- pentanoic acid (7 g, 0.031 mol) in dry toluene (35 ml) and reaction mixture was heated at 75 - 80 °C for 3 hours. Solvent was distilled off at 75 - 80 °C to give 7.58 g (100 %) of the title compound as oil.

Step Π: Preparation of (R),(R)-3-(3-methoxy-phenyI)-2-methyl-pentan-l-oI

To a stirred solution of (R),(R)- 3-(3-methoxy-phenyl)-2-methyl-pentanoyl chloride (7g, 0.029 mol) in dry tetrahydrofuran (33 ml), lithium aluminium hydride (1.66 g, 0.046 mol) was added at 0-5 °C and stirred for 1 hour. Thereafter, reaction mixture was stirred at,20-25 °C for 1 hours and then at 50-55 °C for 1 hour. Reaction mixture was then cooled to 0 to 5 °C and quenched with ethylacetate (10 ml), methanol (10ml) and aqueous sodium hydroxide (5ml, 10%) and stirred for further 1 hour. Solvents were distilled off and resulting residue was cooled to 0 °C. To this, chilled water (50 ml) was added and product was extracted using dichloromethane (3 x 30ml). All the organic extracts were combined, washed with water (2 x 30ml), dried over sodium sulphate and distilled off to give 4.85 g (80 %) of title compound.

(S)(S) isomer, (S)(R) and (R)(S) of 3-(3-methoxy-phenyl)-2-methyl-pentan-l-ol were prepared by following the procedure as given in Example 19; Methods A, B and C starting from corresponding isomer of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid.

Example 20: Preparation of (R), (R)-toluene-4-sulfonic acid 3-(3-methoxy-phenyl)-2-methyl-pentyl ester To a stirred solution of (R), (R)-3-(3-methoxy-phenyl)-2-methyl-pentan-l-ol (4.5 g, 0.022 mol), triemylamine (2.73 g, 0.027 mol) and 4-N,N-dimemylammopyricline (0.66 g, 0.005 mol) in dichloromethane (25 ml), p-toluene sulfonyl chloride (4.74 g, 0.025 mol) was added and reaction mixture was stirred for 6 hours at 25-30 °C. Layers were separated and the organic layer was washed with demineralised water (15 ml). The resulting organic layer was dried over anhydrous sodium sulphate and distilled off to give 7.13 g (91%) of title compound.

Corresponding (S), (S) isomer, (S)(R) and (R) (S) isomer of toluene-4-sulfonic acid 3-(3-methoxy-phenyl)-

2- methyl-pentyl ester were prepared by using corresponding intermediates and following the procedure as given in Example 20.

Example 21: Preparation of (R),(R)-[3-(3-methoxy-phenyl)-2-methyl-pentyl]-dimethyl-amine

A suspension of N,N-dimemylamme-hydrochloride (3.15 g, 0.039 mol), sodium hydroxide (2.32 g, 0.058 mol) in dimethylsulfoxide (35 ml) at 20-25 °C was stirred for 10 minutes. (R)-(R)-Toluene-4-sulfonic acid

3- (3-methoxy-phenyl)-2-methyl-pentyl ester (7 g, 0.019 mol) was then added to the reaction mixture and stirred at 50-55 °C for 2 hours. Thereafter, the reaction mixture was quenched with chilled water (100 ml) at 15 °C and extracted with methyl tertiary butyl ether (3 x 50 ml). Combined organic layer was washed with water (2 x 40ml) and dried over anhydrous sodium sulphate. The resulting organic layer was distilled off to give 4.32 g (95 %) of title compound; [a]_D ^RT= -35.96 (c = 1 %; methanol)

Corresponding (S), (S) isomer, (S)(R) and (R) (S) isomer of [3-(3-methoxy-phenyl)-2-methyl-pentyl]- dime&yl-amine were prepared by using corresponding intermediates and following the procedure as given in Example 21.

Example 22: Preparation of (R), (R)-[3-(3-methoxy-phenyI)-2-methyl-pentyl]-dimethyl-arnine- hydrochloride

To a stirred solution of (R), (R)-[3-(3-memoxy-phenyl)-2-memyl-pentyl]-dimemyl-amine (0.5 g, 0.002 mol) in isopropyl ether (5 ml), isopropyl ether hydrochloride (1 ml, 1 1.7%) was added and stirred for 2 hours at 25-30°C. The resulting product was filtered and dried to give 0.5g (87 %) of the title compound. [a]_D ^RT= -25.12 (c = 0.95%; methanol)

(S), (S) isomer, (S)(R) and (R) (S) isomer of [3-(3-memoxy-phenyl)-2-memyl-pentyl]-dimemyl-amine hydrochloride were prepared by using corresponding intermediates and following the procedure as given in Example 22.

Example 23: Preparation of tapentadol

Method A: A mixture of (R), (R)-[3-(3-memoxy-phenyl)-2-memyl-pentyl]-dimemyl-amine (4 g, 0.017 mol) and aqueous hydrobromic acid (46%, 30ml) was heated under stirring at 100-105 °C for 3 hours and cooled to 20 °C. Thereafter reaction mixture was neutralized with sodium bicarbonate (1.72 g) and the resulting product was extracted with dichloromethane (30 ml). The organic layer was washed with water (20 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off to give 3.6 g (96%) of title compound. The resulting product was stirred in ethyl acetate (5 ml) for 2 hours, filtered and dried to give 2.63 g (70 %) of title compound.

Method B: A mixture of (R), (¾^)-[3-(3-memoxy-phenyl)-2-methyl-pentyl]-dmiethyl-amine (0.3g, 0.001 mol), aqueous hydrochloric acid (10 N, 5ml) and sodium bromide (0.03 g) was heated to reflux and stirred for 8 hours. The reaction mixture was cooled to 20 °C. The excess of acid was degassed, and reaction mixture was neutralized with sodium bicarbonate. The resulting product was extracted with dichloromethane (5ml). The organic layer was washed with water (2 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off to give 0.2 g (71 %) of the title compound.

Method C: A mixture of (R), (R)-[3-(3-memoxy-phenyl)-2-memyl-pentyl]-dmiethyl-amine (0.3g, 0.001 mol), aqueous hydrochloric acid (10N, 5ml) and potassium iodide (0.03 g) was heated to reflux and stirred for 8 hours. The reaction mixture was cooled to 20 °C. The excess of acid was degassed, and reaction mixture was neutralized with sodium bicarbonate. The resulting product was extracted with dichloromethane (5ml). The organic layer was washed with water (2 ml) and dried over anhydrous sodium sulfate .The solvent was distilled off to give 0.21 g (74%) of the title compound.

Method D: : A mixture of (R), (R)-[3-(3-methoxy-phenyl)-2-memyl-pentyl]-dimethyl-amine (0.3g, 0.001 mol), pyridine hydrobromide (0.61 g) and chloroform (4 ml) was heated to reflux and stirred for 8 hours. The reaction mixture was cooled to 20 °C. Water was added to the reaction mixture and layers were separated. Aqueous layer was neutralized with sodium bicarbonate. The resulting product was extracted with dichloromethane (7 ml, containing 10 % tetrahydrofuran). The organic layer was separated and solvent was distilled off to give 0.19 g (68%) of the title compound.

Method E: A mixture of (R), (R)-[3-(3-memoxy-phenyl)-2-methyl-pentyl]-dimethyl-amine (l.Og, 0.004 mol), formic acid (5 ml) and aqueous hydrobromic acid (46%, 1.12 ml, 0.006 mol) was heated under reflux for 5 hours and cooled to 20 °C. Formic acid was distilled from the reaction mixture and aq. ammonia (5 ml) was added to the reaction mixture. Resulting product was extracted with dichloromethane (10 ml). Resulting organic layer was distilled off to give 0.85 g (90%) of the title compound.

Method F: To a mixture of dodecanethiol (2.61g, 0.013 mol) and dichloromethane (10 ml), aluminum chloride (2 g, 0.015 mol) was added at 0 °C. (R),(¾)-[3-(3-memoxy-phenyl)-2-methyl-pentyl]-dimethyl- amine (1 g, 0.004 mol) was added to the reaction mixture and stirred at ambient temperature for 16 hours. Ethanol (10 ml) was added to the reaction mixture, stirred and filtered. Solvents were distilled off from the filtrate and reaction mass was washed with cyclohexane (3 x 2ml). The resulting reaction mass was .dissolved in dichloromethane (7ml) and treated with solid sodium carbonate (2 g). The reaction mixture was filtered and solvents were distilled off from the filtrate to give 0.64 g (68%) of the tide compound. (S), (S) isomer, (S)(R) and (R) (S) isomer of [3-(3-hydroxy-phenyl)-2-memyI-pentyI]-(limemyl-amine were prepared by using corresponding intermediates and following the procedure as given in Example 23- Methods A-F.

Example 24: Preparation of tapentadol hydrochloride

Method A: To a stirred solution of tapentadol (0.25 g, 0.001 mol) in methanol (2 ml) was added isopropyl ether hydrochloride (0.45 ml, 11.7%) and reaction mixture was stirred for 1 hour at 25-30°C. The solvents were distilled off. The residue thus obtained was stirred in ethyl acetate (3 ml) for 2 hours, filtered and dried to give 0.22 g (76%) of the title compound having purity 99.8 % by HPLC; andlOO % by chiral HPLC. [a]_D ^RT= -27.6 (c = 0.97% ; methanol) and M.P. 168-170 °C

Method B: To a mixture of ethanethiol (0.8 g, 0.012 mol) and dichloromethane (10 ml), aluminum chloride (2g, 0.015 mol) was added at 0 °C. The resulting solution was heated to 20-25 °C and (R),(R)-[3-(3- memoxy-phenyl)-2-methyl-pentyl]-dimemyl-amine (1 g, 0.004 mol) was added to the reaction mixture with stirring. The reaction mixture was stirred 4 hours. Thereafter, 2N hydrochloric acid (10 ml) and sodium chloride (3 g) was added to the reaction mixture and degassed by applying vacuum to remove excess hydrochloric acid. The resulting product was extracted with dichloromethane (8 ml, containing 10% tetrahydrofuran). Organic layer was separated and solvents distilled off to give 1.01 g (92 %) of the title compound.

Method C: To a mixture of sodium sulfide (1 g, 0.012 mol) and dichloromethane (10 ml) aluminum chloride (2g, 0.015 mol) was added at 15-20°C. The resulting solution was heated to 20-25 °C and (R),(R)- [3-(3-memoxy-phenyl)-2-memyl-pentyl]-dimemyl-amine (1 g, 0.004 mol) was added to the reaction mixture with stirring. The reaction mixture was stirred 10 hours. Thereafter, 2N hydrochloric acid (10 ml) and sodium chloride (3 g) was added to the reaction mixture and degassed by applying vacuum to remove excess HC1. The resulting product was extracted with dichloromethane (8 ml., containing 10% tetrahydrofuran). Organic layer was separated and solvents distilled off to give 0.98 g (90 %) of the title compound.

(S), (S) isomer, (S)(R) and (R) (S) isomer of [3-(3-hydroxy-phenyl)-2-memyl-pentyl]-dimemyl-aniine hydrochloride were prepared by following the procedure as given in example 24.

Claims

WE CLAIM:

1. A process for the preparation of l-phenyl-3-dimethylarninopropane derivatives of formula I, or its isomers, enantiomers, diastereomers, racemates, solvates, hydrates or pharmaceutically acceptable salts thereof, comprising the steps of:

a), reducing an intermediate of formula Π,

Formula Π

wherein R, can be selected from -OR2, halo, -CH2OR7, SR2, -SOR2, S0₂R₂, -^SOM -M¼ -NR₂R₂ ', - CONR₂R₂ ', carboxylic esters, sulfonate esters or phosphate esters and the like; R' can be selected from

hydrogen, alkyl, aryl, aralkyl, alkaryl,

OR ' can be selected from -NR₂R₂ '; or

R₂ andR₂ ' can be same or different and can be selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl,-ORs, -COR₃, -P(¾(¾-¾) wherein Rsand R4 can be same or different and can be selected from alkyl, aryl, aralkyl, heteroaryl and the like

using a suitable reducing agent;

b). optionally, isolating aldehyde intermediate of formula ΠΙ;

Formula III

wherein Rj is as defined above

c). recovering hydroxy! intermediate of formula IV from the reaction mixture;

Formula IV

wherein Rj is as defined above

d). converting the hydroxyl moiety of intermediate of formula IV into a good leaving group to obtain an intermediate of formula V;

Formula V

wherein Rjis as defined above; and LG is a good leaving group

in the presence of a suitable reagent

e). condensing intermediate of formula V with substituted amine of formula VI,

«6 Formula VI

wherein Rs and Re can be same or different and independently can be selected from hydrogen, alkyl, aryl, aralkyl, alkaryl, SO₂R3, SOiAr, -COR3, -OPOR3R₄, (wherein R₃ andR₄ are as defined above); R₅ and Re can be combined to form a five membered heterocyclic ring or five membered heterocyclic ringfiised with six membered ring, preferably ring can be pyrrolidine-2,5-dione; substituted or unsubstituted isoindole- 1,3-dione; substituted or unsubstituted l,l-dioxo-l,2-dihydro-benzo[dJisothiazol-3-one and the like, wherein substituent can be alkyl, aryl, aralkyl or alkaryl and the like

or salts thereof in the presence of suitable base to form an intermediate of formula VII; and

Formula VII

wherein Rj , R5 and Re are as defined above

f). converting the intermediate of formula VII or salts thereof to 1 -phenyI-3 limethylarninopropane derivatives of formula I or pharmaceutically acceptable salts thereof.

2. The process according to claim 1, wherein in step a) reducing agent is selected from boron compounds such as borane, borane dimethylsulfide; lithium aluminium hydride, vitride, sodium borohydride and the like with or without catalyst; hydrogenation using hydrogen source such as nascent hydrogen in the presence of a suitable catalyst including transition metal catalyst such as nickel, palladium, platinum and the like with or without support (carbon) or as organometallic complexes; in step d) suitable reagent is selected from thionyl halide such as thionyl bromide or thionyl chloride; aliphatic sulfonyl halide such as methanesulfonyl chloride; and aromatic sulfonyl halide such as benzenesulfonyi chloride, 4-mtrobenzenesulfonyl chloride, or p-toluenesulfonyl chloride; phosphorus oxy halide, phosphorus trihalide, phosphorus pentahahde, hydrogen chloride, hydrogen bromide, phosphorus compound of formula P(R)₃ {wherein R is alkyl or aryl or aryloxy] in combination with other reagent selected from CX₄, isocyanates and X_2; such as triphenyl phosphine or P(OPh)₃ in combination with CX₄ or isocyanate or chlorine gas; and the like with or without catalyst; and in step e) suitable base is selected from organic base having general formula NRaRbRc (wherein Ra, ¾, & Rc can be independently selected from hydrogen, straight, branched or cyclic Cj.w alkyl, aryl, heteroaryl, aralkyl, alkaryl, substituted alkyl, substituted aryl, heteroaryl and the like) such as tertiary amines like trialkylamine (triethylarnine, diisopropylethyl amine) and the like; or inorganic base including alkali or alkaline metal carbonate, bicarbonate, hydroxide, hydrides and alkoxides thereof such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate; with or without additives and the like or combination thereof.

3. A process for the preparation of l-phenyl-3→iimemylaminopropane derivatives of formula I, or its isomers, enantiomers, diastereomers, racemates, solvates, hydrates or pharmaceutically acceptable salts

a) , reducing intermediate of formula Π using a suitable reducing agent,

b) . optionally, isolating aldehyde intermediate of formula ID,

c) . recovering hydroxyl intermediate of formula IV from the reaction mixture;

d) . converting the hydroxyl moiety of intermediate of formula IV into a good leaving group to obtain intermediate of formula V in the presence of suitable reagent;

e) . condensing intermediate of formula V with N V limemylamine or salts thereof in presence of suitable base to form compound of formula VIE; and

Formula Vffl

wherein Rji as defined above

f). converting intermediate of formula Vin or salts thereof to l^henyl-3-dimemylaminopropane derivatives of formula I or pharmaceutically acceptable salts thereof.

4. The process according to claim 3, wherein in step a) reducing agent is selected from boron compounds such as borane, borane dimethylsulfide; lithium duminium hydride, vitride, sodium borohydride and the like with or without catalyst; hydrogenation using hydrogen source such as nascent hydrogen in the presence of a suitable catalyst including transition metal catalyst such as nickel, palladium, platinum and the like with or without support (carbon) or as organometallic complexes; in step d) suitable reagent is selected from thionyl halide such as thionyl bromide or thionyl chloride; aliphatic sulfonyl halide such as methanesulfonyl chloride; and aromatic sulfonyl halide such as benzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, or p-toluenesulfonyl chloride; phosphorus oxy halide, phosphorus trihalide, phosphorus pentahalide, hydrogen chloride, hydrogen bromide, phosphorus compound of formula P(R)₃ [wherein R is alky I or aryl or aryloxy] in combination with other reagent selected from C¾, isocyanates and X_2; such as triphenyl phosphine or P(OPh)3 in combination with CX4 or isocyanate or chlorine gas; and the like with or without catalyst; and in step e) suitable base is selected from organic base having general formula NRgRbRc (wherein Ra, & Rc can be independently selected from hydrogen, straight, branched or cyclic C_/.io alkyl, aryl, heteroaryl, aralkyl, alkaryl, substituted alkyl, substituted aryl, heteroaryl and the like) such as tertiary amines like trialkylamine (triethylamine, diisopropylethyl amine) and the like; or inorganic base including alkali or alkaline metal carbonate, bicarbonate, hydroxide, hydrides and alkoxides thereof such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate; with or without additives and the like or combination thereof.

5. The process according to claims 1 and 3, wherein aldehyde intermediate of formula ΙΠ is not isolated.

6. The process according to claims 1 and 3, wherein aldehyde intermediate of formula ΠΙ is isolated.

7. A process for the preparation of tapentadol or pharmaceutically acceptable thereof, comprising the steps of: a), converting an acid intermediate of formula Ha,

CH₃ Formula Ha

in to hydroxyl intermediate of formula IVa;

Formula IVa

b). reacting hydroxyl intermediate of formula IVa with a suitable reagent to form a intermediate of formula Va;

Formula Va

wherein LG is a good leaving group;

c). condensing intermediate of formula Va with NN-dimemylamine or salts thereof in the presence of suitable base to in form dimethylamino intermediate of formula Villa,

Formula V illa

or salts thereof; and d). converting intermediate of formula Villa or salts thereof into tapentadol of formula I or its pharmaceutically acceptable salts thereof.

8. The process according to claim 7, wherein in step b) suitable reagent is selected from thionyl halide such as thionyl bromide or thionyl chloride; aliphatic sulfonyl halide such as methanesulfonyl chloride; and aromatic sulfonyl halide such as benzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, or p-toluenesulfonyl chloride; phosphorus oxy halide, phosphorus trihalide, phosphorus pentahalide, hydrogen chloride, hydrogen bromide, phosphorus compound of formula P(R)₃ [wherein R is alkyl or aryl or aryloxy] in combination with other reagent selected from CX₄, isocyanates and X_2; such as tnphenyl phosphine or P(OPh)₃ in combination with CX₄ or isocyanate or chlorine gas; and the like with or without catalyst; and in step c) suitable base is selected from organic base having general formula NRaR_bR_c (wherein R_a, R_b, & R_c can be independently selected from hydrogen, straight, branched or cyclic Ci-w alkyl, aryl, heteroaryl, aralkyl, alkaryl, substituted alkyl, substituted aryl, heteroaryl and the like) such as tertiary amines like trialkylamine (triemylamine, diisopropylethyl amine) and the like; or inorganic base including alkali or alkaline metal carbonate, bicarbonate, hydroxide, hydrides and alkoxides thereof such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate; with or without additives and the like or combination thereof.

9. A process for the preparation of l^henyl-3-dimemylaminopropane derivatives of formula I or pharmaceutically acceptable salts thereof, comprising steps of:

a), preparing hydroxy! intermediate of formula TV,

Formula IV

wherein Rj is as defined above

starting from intermediate of formula Π

Formula Π

wherein Rj and R ' are as defined above b). converting the same in to l-phenyl-3-dimethylaminopropane derivatives of formula I or pharmaceutically acceptable salts thereof

10. The process according to claim 9, wherein preparation of hydroxyl intermediate of formula IV, comprising the steps of:

a) , reducing intermediate of formula II using a suitable reducing agent; and

b) . isolating hydroxyl intermediate of formula IV there from.

11. The process according to claim 10, wherein in step a) reducing agent is selected from boron compounds such as borane, borane dimethylsulfide; lithium aluminium hydride, vitride, sodium borohydride and the like with or without catalyst; hydrogenation using hydrogen source such as nascent hydrogen in the presence of a suitable catalyst including transition metal catalyst such as nickel, palladium, platinum and the like with or without support (carbon) or as organometallic complexes

12. The process according to claim 9, wherein preparation of hydroxyl intermediate of formula IV, comprising the steps of:

a), esterifying intermediate of formula lib (a variant of intermediate of formula II, wherein R ' is hydrogen and Ri is OCH₃)

Formula lib

to form ester intermediate of formula lib' using a suitable reagent; and

wherein R " is alk

are as defined above

b). reducing ester intermediate of formula lib' with a suitable reducing agent to form hydroxyl intermediate of formula IV.

13. The process according to claim 12, wherein in step a) suitable reagent is alcohol of formula R"OH (wherein R" is as defined above) and a suitable catalyst selected from Lewis acid such as borane trifluoride. diethyl ether complex; boric acid and the like; or acids such as carboxylic acids, sulfonic acids, phosphoric acid, sulfuric acid or derivative thereof; or acetic anhydride, thionyl chloride, boric acid and the like; and in step b) suitable reducing agent is selected from reducing agent is selected from boron compounds such as borane, borane dimethylsulfide; lithium aluminium hydride, vitride, sodium borohydride and the like with or without catalyst; hydrogenation using hydrogen source such as nascent hydrogen in the presence of a suitable catalyst including transition metal catalyst such as nickel, palladium, platinum and the like with or without support (carbon) or as organometallic complexes.

14. The process according to claim 9, wherein preparation of hydroxyl intermediate of formula IV, comprising the steps of:

a), activating the carboxyl moiety of intermediate of formula II (wherein R ' is hydrogen and Rj is

OCHs) using a suitable reagent to form activated intermediate of formula,

wherein Xis hal , - O-COR3, -O -SO₂R_3, , wherein R3 is as defined above

b). reducing activated acid intermediate to form hydroxyl intermediate of formula IV.

15. The process according to claim 14, wherein in step a) suitable reagent is selected from thionyl halide such as thionyl chloride, thionyl bromide; phosphorus trihalides, phosphorus oxy halides, compound of general formula R'COX, R'S(¼X, R'NCN {wherein in R ' is as defined above and Xis halo group such as chloro, bromo.fluroro and the like) such as NJV-dicyclohexylcarbodiirnide; and in step b) reducing agent is selected from boron compounds such as borane, borane dimethylsulfide; lithium aluminium hydride, vitride, sodium borohydride and the like with or without catalyst; hydrogenation using hydrogen source such as nascent hydrogen in the presence of a suitable catalyst including transition metal catalyst such as nickel, palladium, platinum and the like with or without support (carbon) or as organometallic complexes.

16. A process for the preparation of 1 ^henyl-3-dimemylaminopropane derivatives of formula I,

Formula I

or pharmaceutically acceptable salts thereof which comprises step of demethylating methoxy intermediate of formula Vmb,

Formula VHIb

including any of the isomers^' such as (R)(R), (S)(S), (S)(R), (R)(S) isomer or mixture thereof in any proportion or racemates, salts, solvates, and hydrates thereof

using a suitable demethylating agent selected from high molecular weight alkane or arene thiolate anions such as ethanethiol, dodecanethiol or sodium sulfide with or without trimethyl silyl chloride or aluminium halide; boron trihalide, boron trihalide-dialkyl sulfide complex; aluminium halide, tri isobutyl aluminium hydride; metal halide such as lithium iodide in combination with 2,4,6-collidine, lithium chloride in dimethylformamide, lithium triethyl borohydride, lithium tri sec-butyl borohydride; sodium iodide in combination with trimethyl silyl chloride; or sodium iodide, sodium bromide, potassium iodide in combination with inorganic acid such as hydrochloric acid.; pyridine or salts thereof such as pyridine hydrobromide; hydrobromic acid with carboxylic acid such as formic. acid, acetic acid and the like or combination thereof.

17. A process for the preparation of acid intermediate of formula Ha, comprising the steps of

a) , providing a solution of racemic compound of formula lib in an organic solvent;

b) . adding a suitable resolving agent sufficient in amount to form diastereomeric salts;

c) . isolating (R),(R)-diastereomeric salt from the reaction mixture;

d) . optionally, purifying (R),(R)-diastereomeric salt;

e) . neutralizing (R),(R)-diastereomeric salt with an acid; and

f) . isolating intermediate of formula Π..

18. The process according to claim 17, wherein in step b) resolving agent is selected from chiral or achiral amine of general formula, R_a'R_b'R_c'CNH₂ wherein R_a Rf,- and Rc- can be same or different and can be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkaryl, substituted or unsubstituted aralkyl and the like; and in step e) acid is selected from organic acid such as R₃COOH, R₃SO₃H (wherein R₃ is as defined above); or inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or nitric acid and the like.

19. An intermediate of formula Π,

Formula Π wherein Rj can be selected from -ORz halo, -CH2OR₂, -SR2, -SOR2, -S0₂R₂, SO3H, -NO?, -NR2R2 ', - CONR₂R₂ ', carboxylic esters, sulfonate esters or phosphate esters and the like;

R ' can be selected from hydrogen, alkyl, aryl, aralkyl, alkaryl, heteroaryl,

OR ' can be selected from -NR₂R2 '; or

R₂ and R₂ ' can be same or different and can be selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, -OR₃, -COR3, -P(¾(%/¾) wherein R₃ and R4 can be same or different and can be selected from alkyl, aryl, aralkyl, heteroaryl and the like

including any of the isomers such as (R)(R), (S)(S), (S)(R), (R)(S) isomer or mixture thereof in any proportion or racemates, salts, solvates, and hydrates thereof.

I. A hydroxy! intermediate of formula IV,

Formula IV

wherein Rj can be selected from -OR₂, halo, -CH₂OR₂, SR_Z SOR2, S0₂R₂, SO₃H, - ¾ -NR₂R₂', - CONR₂R₂ ', carboxylic esters, sulfonate esters or phosphate esters and the like

R₂ and R₂ ' can be same or different and can be selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl,-OR₃,

-COR₃, -P0₃(R3Rf) wherein R₃ and R4 can be same or different and can be selected from alkyl, aryl, aralkyl, _ heteroaryl and the like