WO2011080756A1

WO2011080756A1 - Process for the preparation of 1-phenyl-3-dimethylaminopropane derivatives

Info

Publication number: WO2011080756A1
Application number: PCT/IN2010/000855
Authority: WO
Inventors: Shekhar Bhaskar Bhirud; Perminder Singh Johar; Ekta Sharma; Danish Jamshad; Ramkaran Prajapaty
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2009-12-29
Filing date: 2010-12-27
Publication date: 2011-07-07

Abstract

A process for the preparation of 1-phenyl-3-dimethylaminopropane derivatives of formula (I) and its pharmaceutically acceptable salts thereof from cyano intermediate of formula (II), wherein R₁ can be selected from -OR₂, halo, -CH₂OR₂, -SR₂, -SOR₂, SO₂R₂, -SO₃H, -NO₂, -NR₂R₂', -CONR₂R₂', carboxylic esters, sulfonate esters or phosphate esters, R₂and R₂' can be same or different, and can be selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, -COR₂", -P0₃(R₂")₂ wherein R₂" 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 process for the preparation of l-phenyl-3-dimethylaminopropane derivatives of formula I, and pharmaceutically 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.

Formula la

BACKGROUND OF THE INVENTION

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

Formula la

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 following scheme:

(2R,3R)

The preparation of tapentadol starts from reaction of 3-bromoanisole with l-dimemylamino-2- methylpentan-3-one to form racemic tertiary alcohol intermediate, which is then resolved by chiral HPLC. The resolved intermediate is then converted into the 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 next stage. Hydrochloride formation of the intermediates takes 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 process for preparing racemic 3-(3- methoxyphenyl)-N,N,2- trimethylpentanamine, intermediate of tapentadol by the 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-trimethylpentanamine as outlined below.

(2S-3S) (ZM2RHEM2R) (2R,3R) (2R S) US patent publication 2006/0167318 discloses a process for preparing racemic 3-(3-methoxyphenyl)- NN2-trimethylpentanamine, 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-methoxyphenyl)-N,N,2- trimethylpentanamine as outlined below.

(2I R) (2R,3S)

The above disclosures are silent about the conversion of racemic mixture of 3 -(3- methoxy phenyl)- NN2-trimethylpentanamine 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, 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.

Et₂NH MTBE

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-dimethylaminopropane derivatives. Thus, present invention fulfills the need in the art and provides an industrially advantageous process for the synthesis of 1- phenyl-3-dimethylaminopropane derivatives i.e. tapentadol and its pharmaceutically acceptable salts thereof that do not involve chiral chromatographic technique for the separation of isomers.

OBJECT OF THE INVENTION

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

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

Another object 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-dimethylaminopropane derivatives of formula I and its pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION

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

Formula I

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

The present invention provides a process for the preparation of compound of formula I i.e. l-phenyl-3- dimethylaminopropane derivatives of formula I, including its isomers, enantiomers, diastereomers, racemates, solvates, hydrates or pharmaceutically acceptable salts thereof starting from cyano intermediate of formula II,

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; R₂ and R₂ ' can be same or different and can be selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, -COR₂ ' ', -PO}(R₂ ' ')₂ wherein R₂ ' ' can be selected from alkyl, aryl, aralkyl, heteroaryl and the like

According to one embodiment, present invention provides a process for the preparation of l-phenyl-3- dimethylaminopropane derivatives of formula I, comprising the steps of:

a), reducing a cyano intermediate of formula II using a suitable reducing agent to form an intermediate of formula III,

Formula III

wherein Rj is as defined above

b). reacting the intermediate of formula III with a suitable methylating agent to form an intermediate of formula IV;

Formula IV

wherein R is as defined above

c). converting intermediate of formula IV into l-phenyl-3-dimethylaminopropane derivatives of formula I.

According to one another embodiment, present invention provides a process for the preparation of 1- phenyl-3-dimethylaminopropane derivatives of formula I or pharmaceutically acceptable salts thereof, comprising the steps of:

a), reducing cyano intermediate of formula II using a suitable reducing agent to form intermediate of formula III,

Formula III

wherein R] is as defined above

b). optionally, converting the intermediate of formula III to intermediate of formula V;

Formula V wherein R3 and R4 are nitrogen protecting group, can be same or different and independently can be selected from alkyl, aryl, aralkyl, alkaryl, -SO2R2, -S0₂Ar, -COR₂ ", -,PO_}(R₂ ")₂ (wherein R₂ andR₂ " are as defined above); R3 and R4 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 1 , l-dioxo-1 ,2-dihydro-benzofdJ isothiazol-3-one and the like, wherein substituent can be alkyl, aryl, aralkyl or alkaryl and the like; provided both R and R4 are not methyl group

c) . optionally, deprotecting the intermediate of formula V to form intermediate of formula III, d) . reacting the intermediate of formula III with a suitable methylating agent to form an intermediate of formula IV;

Formula IV

wherein Rj is as defined above

e) . converting intermediate of formula TV into l-phenyl-3-dimethylaminopropane derivatives of formula I.

a), hydrolyzing cyano intermediate of formula II using a suitable reagent to form an acid intermediate of formula VI,

Formula VI

wherein R] is as defined above

b) . optionally, converting acid intermediate of formula VI to corresponding reactive derivative thereof;

c) . reacting acid intermediate of formula VI or reactive derivative thereof with amine of formula VII, ror^Rs

R« Formula VII

wherein R5 and Re can be same or different and independently can be selected from hydrogen, alkyl, aryl, aralkyl, alkaryl, -S0₂R₂, -S0₂Ar, -COR₂ ", -P0₃(R₂ ")₂ wherein R₂ and_, R₂ " are as defined above in the presence of a suitable base to form an amide intermediate of formula VIII,

Formula VIII

wherein Rj_t R$and R are as defined above

d). reducing the amide intermediate of formula VIII with a suitable reducing agent to form a compound of formula IX; and

Formula IX

wherein i?y, R5 and Re are as defined above

e). converting compound of formula ΓΧ to l-phenyl-3-dimemylaminopropane derivatives of formula I According to one specific embodiment, compound 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. According to still another embodiment, present invention provides a process for preparation of tapentadol of formula la, or its pharmaceutically acceptable salts thereof, comprising the steps of:

a) , providing racemic l-phenyl-3-dimethylaminopropane derivative of formula I or its pharmaceutically acceptable salts;

b) . treating with a suitable resolving agent;

c) . isolating tapentadol of formula la from the reaction mixture; and

d) . optionally, reacting resulting tapentadol of formula la with a suitable acid to form its pharmaceutically acceptable salts thereof.

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

Formula X wherein Ri is as defined above; R7 , Rs can be same or different and can be independently selected from -CN, -COOR₉, -COOR₉ ', -S0₂Rio: provided both R₇ and R₈ can not be -SO₂R]₀; R9, Rg ' nd R₁₀ can be same or different and can be selected independently from alkyl, aryl, heteroaryl, aralkyl, alkaryl group

According to one preferred embodiment, present invention provides a process for the preparation of novel cyano intermediate of formula II, comprising the step of de-cyanating the dicyano intermediate of formula Xa (a variant of compound of formula X),

Formula Xa

wherein Ri is as defined above

using a suitable de-cyanating agent.

According to another preferred embodiment, present invention provides a process for the preparation of novel cyano intermediate of formula II from cyanoester intermediate of formula Xb (a variant of compound of formula

Formula Xb

wherein R_/ and R9 is as defined above

The process comprises the steps of:

a), hydrolyzing cyanoester intermediate of formula Xb to form an intermediate of formula XI,

Formula XI

wherein Rj is as defined above

b) . decarboxylating the intermediate of formula XI; and

c) . isolating the compound of formula II from the reaction mixture.

According to another preferred embodiment, present invention provides a process for the preparation of novel cyano intermediate of formula II starting from diester intermediate of formula Xc (a variant of compound of formula X),

Formula Xc

wherein R₉ and Rg ' are as defined above

which comprises the steps of:

a), decarboxylating diester intermediate of formula Xc to form an ester intermediate of formula XII;

Formula XII

wherein Rj is as defined above; R ' can be same as that of R9 or R₉ '; and R R₉ ' are as defined above b) . hydrolyzing ester intermediate of formula XII to form an acid intermediate of formula VI; and c) . converting acid intermediate of formula VI to cyano intermediate of formula II..

According to still another embodiment, present invention provides a process for the preparation of novel intermediate of formula II , which comprises the step of reacting the compound of formula Xd (a variant of compound of formula X),

Formula Xd

wherein Rj and Rio are as defined above

with a suitable desulfonylating agent.

According to yet another embodiment, present invention provides a process for the preparation of novel intermediate of formula II, starting from compound of formula Xe (a variant of compound of formula

X),

Formula Xe

wherein Rj, R ' and Rio are as defined above

which comprising the steps of:

a), desulfonating the compound of formula Xe to form ester intermediate of formula XII;

Formula XII

wherein Ri and R ' are as defined above

b) . hydrolyzing the ester intermediate of formula XII to form acid intermediate of formula VI; and c) . converting acid intermediate of formula VI to cyano intermediate of formula II.

DETAILED DESCRIPTION OF THE INVENTION

As used herein "the compound of formula F', "l-phenyl-3-dimemylaminopropane derivatives of formula I" as well as "all the intermediates" used herein includes their isomers, enantiomers, diastereomers, racemates, salts, solvates, and hydrates thereof.

As used herein, "aliphatic hydrocarbon" includes straight, chain, branched or cyclic C5_i₂ alkane such as n-pentane, n-hexane, n-heptane, cyclohexaneb and the like or mixture thereof.

As used herein, "aromatic hydrocarbon" includes but not limited to toluene, o-xylene, m- xylene, p- xylene, ethyl benzene and the like or mixture thereof.

As used herein, "C4.io ethers" includes but not limited to diethyl ether, diisopropyl ether, methyl tert- butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxy ethane, diphenyl ether and the like or mixture thereof.

As used herein, "halogenated solvents" but not limited to chloroform or dichloromethane and the like or mixture thereof.

As used herein, "C_2-io esters" includes but not limited to ethyl acetate, methyl acetate, isopropyl acetate and the like or mixture thereof.

As used herein, "CMO alcohol" includes but not limited to methanol, ethanol, propanol, isopropanol, n- butanol, isobutanol, tert-butanol;

As used herein, "polyol" includes but not limited to monoethylene glycol, C_3-1o glycol, glucose and the like or mixture thereof.

As used herein, "C_3-1o ketone" includes but not limited to acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone and the like or mixture thereof.

As used herein, "aprotic solvents" includes but not limited to dimethylsulfoxide, N,N- dimethylformamide, N-methylpyrrolidinone, N,N-dimethylacetamide and the like or mixture thereof. As used herein, "nitriles" includes but not limited to acetonitrile, propionitrile and the like or mixture thereof. The present invention provides a process for the preparation l-phenyl-3-dimethylaminopropane derivatives of formula I, or pharmaceutically acceptable salts thereof using novel cyano intermediate of formula II.

Specifically present invention provides a process for the preparation of tapentadol of formula la or its pharmaceutically acceptable salts thereof using cyano intermediate of formula II or from corresponding desired isomer of the novel intermediates or/and salts thereof.

According to one embodiment, process for the preparation of compound of formula I involves the reduction of the .cyano intermediate of formula II using a suitable reducing agent to form a intermediate of formula III.

Generally, the process involves the reaction of compound 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 reducing agent employed for the reaction can be selected from reducing agents known in the art that can be effectively used for the purpose of reduction of nitrile to primary amine group. Preferably, reducing agent includes boron compounds such as borane, BH₃-Lewis base complex; borane tetrahydrofuran (BH₃.THF); borane complex with substituted amine (BH₃.NR R R , wherein R , R and R are alkyl, aryl, aralkyl, or alkaryl and the like), borane complex with substituted phosphine (BH₃.PR R R , wherein R , R and R are alkyl, aryl, aralkyl, or alkaryl and the like), borane dimethylsulfide; metal hydride such as lithium aluminium hydride; alkali or alkaline metal borohydride such as potassium borohydride, sodium borohydride; with or without additives; or Red-Al and the like. 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 or other methods reported in the art such as in R.C. Larock; Jerry March etc. The role of solvent in the reaction mixture is not critical. Solvent employed for the reaction includes but not limited to aliphatic hydrocarbon (straight, chain, branched or cyclic C_5-i₂ alkane), aromatic hydrocarbon, C_4-io ethers, halogenated solvents and the like or mixture thereof. After completion of the reaction, reaction mixture can optionally be quenched, whenever required. The quenching agent employed for the reaction can be selected from any reagent that can destroy unreacted or excess of reducing agent present in the reaction mass. Quenching agent employed for the reaction includes inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and the like; or ammonium halide; or organic acid such as carboxylic acid, alkyl or aryl sulfonic acids, and the like. Quenching agent can be used as such or as mixture with a suitable solvent such as water, C_2-io esters; Ci-io alcohol such as methanol, polyol; C_3-1o ketone such as acetone and the like or mixture thereof. The intermediate of formula III can be isolated from the reaction mixture or can be proceeded as such for the further reaction. Preferably, intermediate of formula III can be isolated by basifying aqueous layer containing the desired product with a base followed by extraction with a suitable water immiscible solvent which includes but not limited to halogenated solvent; C4_io ethers and the like or mixture thereof. Organic layer can be optionally washed with water and/or dried. Desired intermediate of formula III can be isolated from the organic layer by suitable techniques such as distillation, evaporation and the like. The isolated intermediate of formula III, 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.

Cyano intermediate of II used for the present invention can be selected from its specific isomer such as (R)(R), (S)(S), (R)(S), (S)(R) or mixture of two or more in any proportion which on reduction yields corresponding isomer of compound of formula III.

The compound of formula III (which includes (R)(R) or (S)(S) or (R)(S) or (S)(R) isomers or mixture of two or more isomers in any proportion), thus prepared can be optionally converted to corresponding isomer of compound of formula V, which is further converted back to compound of formula III to enhance the chemical or chiral purity of the compound of formula III and/or to minimize the presence of undesired impurities.

Generally, process involves reaction of compound of formula III with a reagent that can protect the amine group. The reaction can be carried out in the presence of a suitable reagent at a temperature of - 30 to 170 °C for few minutes to several hours, preferably till completion of reaction. The nitrogen protecting groups are well known in the art; therefore, suitable reagent can be selected from any reagent known in the art that can fulfill the same purpose based upon the nature of the protecting group to be incorporated. Any reagent that can incorporate any of the group selected among alkyl, aryl, aralkyl, alkaryl, -S0₂R₂, -S0₂Ar, -COR₂", - -P0₃(R₂")2 ; -COOR₂" and -CONR₂R₂" to the amine group of compound of formula III or reaction can employ a reagent that can result in the formation of five membered heterocyclic ring or five membered heterocyclic ring fused with six membered ring through the nitrogen atom of the amine group, preferably ring formed is pyrrolidine-2,5-dione; substituted or unsubstituted isoindole-l,3-dione; substituted or unsubstituted l,l-dioxo-l,2-dihydro- benzo[d]isothiazol-3-one and the like, (wherein R2_, and R₂ " and substituents are as defined above). Specifically, the reagent employed can be selected from but not limited to formaldehyde with formic acid; alkyl halide, aryl halide, aralkyl halide, alkyl sulfate, aryl sulfate, aralkyl sulfate, alkyl phosphates, aryl phosphates, aralkyl phosphates, sulfonyl halides, acyl halide, phosphoryl halide, tert- butyldicarbonate; alkyl or arylhaloformate such as benzylchloroformate, ethylchloroformate and the like, preferably reagent employed is selected from benzyl bromide and the like. The reaction is advantageously carried out in the presence of a suitable base selected from alkali or alkaline metal hydroxide, carbonate, bicarbonates, alkoxide thereof such as potassium carbonate and the like. Suitable solvent used for providing reaction media includes but not limited to aliphatic hydrocarbon, C_4-io ethers, C_2-io esters, halogenated solvents, aprotic solvents such as dimethylsulfoxide, N,N- dimethylformamide, N-methylpyrrolidinone, Ν,Ν-dimethylacetamide; nitriles, sulfolane and the like or mixture thereof. The intermediate of formula V 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, intermediate of formula V can be isolated from the reaction mixture by layer separation. Organic layer can be optionally washed with water and/or dried over sodium sulfate. Intermediate of formula V can be isolated from the resulting organic layer by the removal of solvent using suitable techniques such as evaporation, distillation and the like. The isolated intermediate of formula V can optionally be purified to enhance the purity or to remove the impurities present in the product.

Wherever intermediate of V thus prepared by the present invention is mixture of two or more isomers, It can be optionally resolved to give a specific isomer of compound of formula V (including (R)(R) or (S)(S) or (R)(S) or (S)(R) isomers which may or may not contain other isomeric impurities). Specifically, (R)(R) isomer of compound of formula V can be prepared either from corresponding isomer of compound of formula III or by the resolution of corresponding racemate, and finally yields tapentadol of formula la, or its pharmaceutically acceptable salts thereof. Resolution can be carried out by any suitable resolution method known in the art.

The compound of formula V is then converted back to compound of formula III by deprotecting the amine group.

Generally, process involves conversion of tertiary amine to primary amine by deprotection of the amine group. The process involves removal of R₃ and R» amine protecting groups by using any suitable reagent known in the art for the deprotection of amine functional group. Usually process involves dealkylation, dearylation, de-aralkylation, 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, the deprotecting reagent can be selected among borane compounds like borane trihalide; beryllium compounds such as beryllium 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 hydrogenolysis of compound of formula V using a suitable catalyst. The catalyst includes transition metals with or without support (carbon) such as palladium, platinum, nickel and the like. Solvent used during the deprotection reaction includes but not limited to alcohols, aliphatic or aromatic hydrocarbon and the like or mixture thereof. 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 III. After the completion of reaction, reaction mixture can be filtered off to remove the catalyst whenever deprotection is carried out using hydrogenation in the presence of catalyst. The compound of formula III can be isolated from the reaction mixture by the suitable methods known in the art such as distillation, evaporation and the like or can be proceeded as such for the further reaction. The isolated intermediate of formula III can optionally be purified to enhance the purity or to remove the impurities, present in the intermediate of formula III.

The compound of formula III (including (R)(R) or (S)(S) or (R)(S) or (S)(R) isomers or mixture of two or more in any proportion) prepared by any of the above method, is further converted to corresponding isomer of compound of formula IV using a suitable methylating reagent.

Generally, the process involves the reaction of compound of formula III with a suitable methylating reagent in a suitable solvent at a temperature of 0 °C to 180°C till the completion of 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 III using a reagent selected from formaldehyde in combination with formic acid or metal hydride or Pd/C with hydrogen pressure, 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 can be chosen on the basis of the reagent employed, preferably suitable solvent includes but not limited to C_4-io ethers, aromatic or aliphatic hydrocarbons, halogenated solvents, C₂÷io esters, C_3-io ketone, 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 IV can be isolated from the reaction mixture by using any conventional technique known in the art or used as such for the further reaction. The compound of formula IV can be optionally purified to increase the purity of the compound as well as to minimize the presence of impurities.

The present invention provides the conversion of compound of formula IV (including (R)(R) or (S)(S) or (R)(S) or (S)(R) isomers or mixture of two or more in any proportion) to corresponding isomer of 1- 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 effect the other functionalities of compound of formula IV.

In one variant, the compound of formula IV (wherein Rj is OR₂, wherein R₂ is as defined above) has structure of formu

Formula IVa

wherein R₂ is as defined above

which 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, the deprotection reaction involves the removal of R₂ group by any suitable reagent known in the art for the deprotection of O-protecting group. Usually the process involves the 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 the 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 beryllium dihalide; thiophenol, lithium diphenylphosphide, aliurunium 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); diisobutylaluminium hydride and the like.

The deprotection reaction may also be effected by the hydrogenolysis of compound of formula IVa using a suitable catalyst. The catalyst includes transition metals with or without support (carbon) such as palladium, platinum, nickel and the like. Solvent used during the deprotection reaction can be selected from aliphatic or aromatic hydrocarbon, C_4-io ether, C_2-io ester, C_MO alcohol, C_3-io ketone, halogenated solvent, nitrile, aprotic solvent and the like or mixture thereof. 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. In another variant, the compound of formula IV (wherein Ri is halo) has the structure of formula IVb,

Formula IVb

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

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 IVb 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 aliphatic or aromatic hydrocarbon, C4_io ether, C_2- io ester, halogenated solvent, nitrile, such as dimethylsulfoxide, dimethylformamide, N- methylpyrrolidinone; sulfolanes and the like or mixture thereof. l-Phenyl-3-dimethylaminopropane 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 IVb is first converted to compound of formula IVa then to l-phenyl-3-dimethylaminopropane derivatives of formula I.

Generally, the process involves the reaction of compound of formula IVb 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, aryloxide, substituted alkoxide, substituted aryloxide such as, sodium methoxide; with or without additives. The reaction can be carried out in a solvent that includes but not limited to aliphatic or aromatic hydrocarbon, C4-10 ether, C_2-1o ester, halogenated solvent, nitrile, aprotic solvents such as dimethylsulfoxide, dimethylformamide, N-methylpyrrolidinone; and the like or mixture thereof. The compound of formula IVa can be isolated from the reaction mixture by using any conventional technique known in the art.

The compound of formula IVa, can be further converted to l-phenyl-3-dimethylaminopropane derivatives of formula I by the method already disclosed in the present invention or method known in the art.

In yet another variant, the compound of formula IV (wherein Rj is -SO3H) can be converted to 1- phenyl-3-dimethylaminopropane derivatives of formula I on heating its alkali metal salts.

Similarly, the compound of formula IV (wherein Rj is -SO₂R₂; R₂ is as defined above) can be first converted to corresponding sulfonic acid using a suitable reagent known in the art such as alcoholic alkali metal hydroxide which include potassium hydroxide in halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride and the like to form corresponding sulfonic acid derivatives. The resulting sulfonic acid derivative may be then converted to l-phenyl-3- dimethylaminopropane derivatives of formula I on heating its alkali metal salts.

In still another approach, the compound of formula IV (wherein Ri is SR2; R2 is as defined above) can be first converted to corresponding sulfoxides or sulfones using reagent such as hydrogen peroxide and potassium permanganate which is then finally converted to l-phenyl-3-dimethylaminopropane derivatives of formula I.

In still another approach, the compound of formula IV (wherein R_/ is selected from carboxylic esters, sulfonate esters or phosphate esters) can be converted to l-phenyl-3-dimethylaminopropane derivatives of formula I using alkali metal hydroxides.

Yet another way compound of formula IV (wherein Ri is -CH₂OR2, wherein R₂ is as defined above) can be first converted to corresponding aldehyde using oxidizing agent which is then finally converted to compound of formula I using hydrogen peroxide in combination with alkali metal hydroxides. Oxidizing agent can be selected from the reagent known in the art for the same purpose and preferably, active manganese dioxide can be used.

Yet another approach, the compound of formula IV (wherein Rj is -NO ₂, can be converted to compound of formula I using the method known in the art for the same purpose.

Similarly other R_\ group can be converted to hydroxy group by using the reagent known in the art and selected upon the basis of Ri group to be converted.

According to another embodiment, present invention provides a process for the preparation of 1- phenyl-3-dimemylaminopropane derivatives of formula I or pharmaceutically acceptable salts thereof by hydrolyzing the cyano intermediate of formula II (including (R)(R) or (S)(S) or (R)(S) or (S)(R) isomers or mixture of two or more in any proportion) to give corresponding isomer of acid intermediate of formula VI.

Generally, the process involves the synthesis of acid intermediate of formula VI by hydrolyzing the cyano intermediate of formula II under suitable conditions. The reagent employed for the reaction can be selected from any reagent known in the art that can effectively hydrolyse cyano group to acid 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 alkali or alkaline metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium 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 acid intermediate of formula VI. The solvent employed for the reaction includes but not limited to water, halogenated solvents, C_2-io esters, C_3-io ketone, C4.J_O ethers such as tetrahydrofuran, aliphatic or aromatic hydrocarbon, nitriles, aprotic solvent, alcohols, polyol and the like or mixture thereof. The compound of formula VI, 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. After the completion of the reaction, reaction mixture can be optionally washed with water and/or water immiscible solvent. Desired product can isolated from the acidic aqueous layer by extraction with water immiscible solvent. Aqueous layer can be adjusted to suitable pH prior to the extraction with a water immiscible solvent whenever reaction is carried out using basic hydrolysis. Acid intermediate of formula VI can be isolated from the resulting solution by suitable techniques such as distillation, evaporation and the like.

Alternatively, acid intermediate of formula VI can be prepared from the cyano intermediate of formula II by optionally isolating corresponding amide intermediate. The isolated acid intermediate of formula VI 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.

The acid intermediate of formula VI (including (R)(R) or (S)(S) or (R)(S) or (S)(R) isomers or mixture of two or more in any proportion) or its reactive derivative thereof can be further treated with amine of formula VII, to form corresponding isomer of amide intermediate of formula VIII.

Generally, the process involves the conversion of acid intermediate of formula VI to its reactive derivatives, which includes but not limited to acid halides, organic acid anhydrides, mixed acid anhydride, cyclic carboxy-anhydrides, active amides or esters, triazole such as benzotriazole or other groups as described in "Comprehensive Organic Transformation by R.C. Larock". The reactive derivative of formula VI can be prepared by reaction of acid intermediate of formula VI with an activating agent selected from oxalyl chloride, phosphorous trihalide, phosphorous pentahalide, thionyl halide, organic acid halides like acetyl chloride, pivaolyl chloride, C_2-8 alkyl chloroformate or aryl chloroformate, Lewis acid like boric acid or 4-(4,6-dimethoxy-l,3,5-triazine-2-yl)-4- meftylmorpholinium chloride and the like. The reaction can be carried out using a suitable activating agent in suitable solvent at a temperature of -40 °C to 180°C. Suitable solvents include but not limited to water, C_4-io ethers, aliphatic or aromatic hydrocarbon solvents, halogenated solvents, nitriles, C|.io alcohols, C_3-10 ketone, C_2-io esters and the like; or mixture thereof. The reactive derivative of acid intermediate of formula VI, can be isolated from the reaction mixture or can be proceeded in situ to undergo reaction with amine of formula VII in the presence of suitable base in a solvent at a temperature of -10 °C to 120°C for few minutes to few hours, preferably till the completion of the reaction. Base employed can be organic or inorganic base. Organic base includes trialkylamines, substituted amines and the like; and inorganic base includes alkali or alkaline metal hydroxide, alkoxide, hydride, carbonate, bicarbonate thereof such as sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. The amidation reaction can be carried out in a solvent that includes but not limited to water, C_4-io ethers, aliphatic or aromatic hydrocarbon solvents, halogenated solvents, nitriles, Ci_-10 alcohols, C_3-io ketone, C_2-io esters, aprotic solvents such as dimethylformamide, dimethylsulfoxide, and the like or mixture thereof. After completion of the reaction, the amide intermediate of formula VIII can be isolated from the reaction mixture by using any conventional technique known in the art or can be used in situ for the further reaction. Preferably, intermediate of formula VIII can be isolated from the reaction mixture by the layer separation. Organic layer can be optionally washed with suitable acid and/or water and/or dried. Amide intermediate of formula VIII can be isolated from the organic layer by suitable techniques such as distillation, evaporation and the like. Isolated amide intermediate of formula VIII can be optionally purified to enhance the purity.

The amide intermediate of formula VIII (including (R)(R) or (S)(S) or (R)(S) or (S)(R) isomers or mixture of two or more in any proportion), thus prepared, can be further reduced to form corresponding isomer of compound of formula IX.

Generally, the process involves the reaction of the compound of formula VIII with a suitable reducing agent at a temperature of -20 °C to 180 °C for few minutes to few hours, preferably till the completion of the reaction. The reducing agent employed for the reaction can be selected from the reducing agents known in the art that can effectively serve the purpose of reduction. Preferably, reducing agent includes boron compounds such as borane; or borane-Lewis base complex, borane tetrahydrofuran (BH₃.THF); borane complex with substituted amine (BH3.NR R R , wherein R , R and R are as defined above), borane complex with substituted phosphine (BH₃.PR R R , wherein R , R and R are as defined above), borane dialkylsulfide such as borane dimethylsulfide; diborane; metal hydride such as lithium aluminium hydride; alkali or alkaline metal borohydride such as potassium borohydride, sodium borohydride; with or without additives and the like. The reduction reaction can be carried out by hydrogenation using hydrogen source such as nascent hydrogen in the presence 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 and the like. The presence or absence of solvent in the reaction mixture is not critical. The solvents employed for the reaction includes but not limited to aliphatic or aromatic hydrocarbon, C_4-io ethers and the like or mixture thereof. After completion of the reaction, intermediate of formula DC can be isolated from the reaction mixture or can be proceeded as such for the further reaction. The isolated intermediate of formula EX, if desired, can be purified using a suitable solvent or any other purification method can be employed to enhance the purity or to minimize the presence of impurities in the intermediate.

Alternatively, the amide intermediate of formula VIII (wherein Ri is—NO ₂) has the structure of formula Villa,

Formula Villa wherein R₅ and Re are as defined above

can be converted to compound of formula IX (wherein Ri is hydroxy) through intermediate of formula VHIb,

Formula VHIb wherein R5 and R are as defined above

Generally, the reaction involves the reduction of compound of formula Villa using a suitable reducing agent at a temperature of -50 °C to 150 °C for few minutes to few hours, preferably till the completion of the reaction. The reducing agent employed for the reaction can be selected from the reducing agents known in the art that can be used effectively for the purpose of reduction of nitro group to amine. Preferably, reducing agent includes Raney Ni, palladium, platinum with or without support (carbon) and the like. The presence or absence of solvent in the reaction mixture is not critical. The solvents employed for the reaction includes but not limited to water, CM_O alcohols, C_2-io esters and the like or mixture thereof. After the completion of the reaction, corresponding amine intermediate can be isolated from the reaction mixture or can be proceeded as such for the further reaction. The resulting amine intermediate is then diazotized with suitable diazotizing reagent in the presence of a suitable acid for few minutes to several hours, preferably till the completion of the reaction. Diazotization reagents employed for the reaction includes nitrous acids, alkyl nitrites, alkali metal salt of nitrous acid, nitrogen dioxide, nitrosyl chloride; and the like. Preferably, the source of nitrous acid employed in the reaction is alkali metal salt of nitrous acid like sodium nitrite, which can be used as such, or solution thereof with water. Suitable acid used for the reaction can be organic or inorganic acid. Organic acid includes carboxylic acid preferably lower alkanoic acid and the like; and inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like or combination thereof. The suitable solvents employed for the reaction is water. As the diazo intermediates are unstable, so it is advantageous to proceed further without the isolation of diazo intermediate. Thereafter, reaction mixture is treated with water or a suitable base such as alkali or alkaline metal hydroxide to form compound of formula Vlllb. Reaction can be carried out at a temperature of -20°C to 80°C for few minutes to few hour, preferably till the completion of the reaction. The solvent employed for the reaction includes but not limited to C_3-1o ketone, nitriles, C -io ether, C_2-1o ester, halogenated solvents and the like or mixture thereof. The resulting intermediate of formula Vlllb is then converted to compound of formula DC (wherein Rj is OH) by the reduction of carbonyl group by employing any reagent known in the art or by the method as already described in the present invention.

Similarly, the amide intermediate of formula VIII (wherein Rj is selected from halo, -OR₂, -CH₂OR₂, - SR₂, -SOR2, -SO2R2, -SO3H, -NO2, -NR2R2 ', -CONR2R2 ', carboxylic esters, sulfonate esters or phosphate esters and the like) can be first converted to intermediate of formula IX (wherein Ri is hydroxy) through intermediate of formula Vlllb and then finally converted to l-phenyl-3- dimethylaminopropane derivatives of formula I.

The compound of formula IX can be further converted l-phenyl-3-dimethylaminopropane derivatives of formula I and its pharmaceutically acceptable salts thereof.

In one preferred embodiment, the compound of formula IX (wherein R5, Ri are hydrogen, including (R)(R) or (S)(S) or (R)(S) or (S)(R) isomers or mixture of two or more in any proportion) has the structure of formula ΙΠ that can be converted to corresponding isomer of compound of formula IV by using methylating agent and then to l-phenyl-3-dimethylaminopropane derivatives of formula I by the method as already described in the present invention. In another preferred embodiment, the compound of formula IX (wherein R5, Re are methyl, including (R)(R) or (S)(S) or (R)(S) or (S)(R) isomer or mixture of two or more in any proportion) has the structure of formula IV that can be converted to corresponding isomer of l-phenyl-3- dimethylaminopropane derivatives of formula I by the method as already described in the present invention.

In still another embodiment, the compound of formula ΓΧ (wherein R5 and Re are as defined above, provided both can not be methyl, including (R)(R) or (S)(S) or (R)(S) or (S)(R) isomers or mixture of two or more in any proportion) has structure of formula V that can be converted first to corresponding isomer of compound of formula III, which is then converted to compound of formula IV and final conversion to l-phenyl-3-dimethylaminopropane derivatives of formula I by the method as already described in the present invention.

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

The final compound of the present invention contains two asymmetric carbon atoms in their molecules, and can thus form optical isomers. Similarly, the intermediates employed for the synthesis also contain asymmetric carbon in their molecule, and can thus form optical isomers.

Accordingly, the present invention includes all possible stereoisomers of compound of formula I as well as of intermediates. It also includes not only racemic compounds, or racemic mixtures thereof, but also 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 the corresponding racemic product 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.

According to another embodiment, present invention provides a process for preparation of specific isomer of acid intermediate of formula VI by resolution of corresponding racemic compound.

Generally, process of resolution involves formation of diastereomeric salt of racemic compound of formula VI in a suitable solvent using a suitable resolving agent, preferably optically active amine. The resolving agent used for resolution of compound of formula VI can be selected from the reagent known and preferably can be selected from chiral or achiral amine of general formula, R_aR_bRcCNH₂ wherein R_a, R_b 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 R R_b 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, 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, cinchonidine, cinchonine, quinine, quinidine, brucine, strychinine, 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, Ci_-10 alcohols; C_4-io ethers; halogenated solvents; aliphatic or aromatic hydrocarbon solvents; nitriles; C_2-8 esters; C_3-8 ketones; and the like or mixture thereof. Solvent details are same as given above. 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 (RT) 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 VI 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 VI. The salt thus prepared can be optionally crystallized with a suitable solvent to enhance the enantiomeric purity of the product. Suitable solvent used for the purification can be selected from the solvents as given above.

A specific isomer of intermediate of formula VI can be recovered from the corresponding diastereomeric salt by its hydrolysis using a suitable acid.

Generally, hydrolysis 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 includes organic acid; or inorganic acid. After completion of reaction, layers were separated. Acid intermediate of formula VI can be isolated from the resulting organic layer by the removal of solvent using suitable techniques such as evaporation or distillation and the like.

Specific isomer of compound of formula VI (including (S)(S), (S)(R) or (R)(S) or (R)R) isomer which may or may not contain other isomeric impurities ) can be converted further to corresponding isomer of compound of formula I or salts thereof. Specifically (R)(R)-isomer of acid intermediate of formula VI yield tapentadol or pharmaceutically acceptable salts thereof by sequence of reaction as described by the present invention.

Similarly resolution of any of the intermediate during the synthesis can be carried out and proceeded to form specific isomer of l-phenyl-3-dimethylaminopropane derivatives of formula I, preferably tapentadol of formula la.

According to another embodiment, present invention provides that l-phenyl-3-dimemylaminopropane 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 or by performing resolution at the final stage.

According to another embodiment, when l-phenyl-3-dimethylaminopropane derivatives of formula I prepared by the processes of present invention is racemic then it can be converted to tapentadol of formula la by resolution of racemic product.

Generally, the process of resolution comprises dissolving the racemic mixture in suitable solvent and addition of a suitable resolving agent. Suitable solvent can be selected on the basis whether diastereomeric salt precipitates out differently. The separation may result simply by stirring at a suitable temperature in a solvent until one of the salts preferentially precipitate out. Purification of diastereomeric salt is possible by crystallization in a suitable solvent. Preferably, water, _\. o alcohols; C_4-io ethers; halogenated solvents; aliphatic or aromatic hydrocarbon solvents; nitriles; C_2-8 esters; C_3-8 ketones; aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidinone and the like or mixture thereof. Thereafter, free base can be liberated from its salt using a suitable base. The diastereomeric salt is dissolved or suspended in a mixture of water and organic solvent and is neutralized with a base under stirring, the free base is obtained after separation of aqueous layer and evaporation of the organic solvent.

Suitable base for the hydrolysis of diastereomeric salt includes alkali (lithium, sodium or potassium and the like) or alkaline metal (calcium, magnesium and the like) hydroxides, carbonates, bicarbonates, hydride and alkoxides thereof in aqueous medium at temperature varying between -20 to 150 °C. The solvents used during the resolution includes but not limited to water, C_4-io ethers; halogenated solvents; aliphatic or aromatic hydrocarbon solvents; nitriles; C_2-8 esters; C_3-8 ketones; and the like or mixture thereof. The resolution can be accomplished at temperature from -20 °C to 150°C or reflux temperature of the solvent used. Suitable resolving agent employed can be chiral acid reagents that include D or L diaroyl acid such as dibenzoyl tartaric acid; D or L camphor sulfonic acid, D or L mandelic acid and the like or any other reagent suitable for the chiral separation, known in the art.

These terms and 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 stereoisomer may also be prepared synthetically from the appropriate stereochemically pure starting materials, or by using stereoselective reactions.

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; 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. According to yet another embodiment, present invention provides a process for the preparation of novel cyano intermediate of formula II starting from compound of formula X.

According to one preferred embodiment, present invention provides a process for the preparation of intermediate of formula II starting from the compound of formula X (wherein both R₇ and R are cyano group) which has structure of formula Xa.

The process involves selective decyanation of dicyano intermediate of formula Xa to give cyano intermediate of formula II.

Generally, the process involves the reaction of dicyano intermediate of formula Xa with a suitable de- cyanating agent at a temperature of -20°C to 180°C for few minutes to few hours preferably, till the completion of the reaction. However, reaction temperature and other conditions can be varied depending upon the nature of de-cyanating agent employed. The de-cyanating agent employed for the reaction can be selected from the reagents known in the art that can be used effectively for the purpose of selective removal of one cyanide group. The de-cyanation reaction can be carried out in the presence of a acid, base, tributyl stannate, samarium (II) iodide; organometallic reagent, sodium dithionite, using transition metal catalyst, hydrogenation, azobisisobutyronitrile, tributyltin hydride, diazabicyclo[5.4.0]undec-7-ene and the like or combination thereof. The presence or absence of solvent in the reaction mixture is not critical. The solvents employed for the reaction includes but not limited to C_4-1o ether, aliphatic or aromatic hydrocarbons, halogenated solvent, nitriles, aprotic solvents such as dimethylsulfoxide, N,N-dimethylformamide; C_2-io ester and the like or mixture thereof. After the completion of reaction, intermediate of formula II can be isolated from the reaction mixture or can be proceeded as such for the further reaction. The isolated intermediate of formula II can be, if desired, 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.

According to another preferred embodiment, present invention provides a process for the preparation of intermediate of formula II starting from the compound of formula X (wherein one of the R7 and R& is cyano group and other is -COOR₉) which has structure of formula Xb.

The process involves the hydrolysis of intermediate of formula Xb to give compound of formula XI which is then decarboxylated to give cyano intermediate of formula II.

The process involves the reaction of compound of formula Xb with a suitable hydrolyzing agent to form compound of formula XI.

Generally, the process involves the hydrolysis of intermediate of formula Xb at a temperature of -20°C to 180°C. Suitable reagent for the hydrolysis can be selected from the reagent known in the art that can serve the purpose; preferably hydrolysis can be carried out in the presence of a suitable acid or base in a suitable solvent. Acid employed in the reaction can be inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic 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. Base can be used as such or in aqueous solution with or without solvents. Organic base includes amine such as ammonia, substituted amine, trialkylamine and the like; inorganic base includes alkali or alkaline metal hydroxide, alkoxide, hydride, carbonate or bicarbonate thereof such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like. Solvents for carrying hydrolysis include water, aliphatic or aromatic hydrocarbon solvents such as toluene; alcohols; ethers; esters, nitriles; aprotic solvents such as dimethylsulfoxide, dimethylformamide, N-methylpyrrolidinone and the like or mixture thereof. The compound of formula XI can be isolated from the reaction mixture or reaction mixture can be used as such for the next stage of the reaction. The compound of formula XI, if desired, can be purified to enhance the purity as well as to remove or minimize the amount of undesired impurities present in the compound of formula XI. The compound of formula XI can be decarboxylated to form compound of formula II.

Generally, decarboxylation reaction can be performed in the presence of suitable solvent with or without catalyst under inert reaction conditions. The suitable solvent can be selected from water, quinoline, dimethylsulfoxide, dimethylformamide, dimethylacetamide, diphenylether, dimethylaniline, pyridine, C_3-io ketone, C3-₁0 ethers, halogenated solvents, C_2-io esters, nitriles, aliphatic or aromatic hydrocarbons, Q.io 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, its salts or a suitable base selected from alkali or alkaline metal carbonates, bicarbonates, hydroxides, alkoxides, hydride thereof or combination thereof. The reaction is preferably conducted at a temperature of about 50 °C to 220°C, preferably at 150 °C to 180°C, preferably till reaction completion. After completion of the reaction, the compound of formula II can be isolated from the reaction mass, by cooling the reaction mass followed by isolation methods known in the art such as extraction with a suitable solvent followed by distillation or filtration.

In another alternate way, compound of formula II can be prepared directly from intermediate of formula Xb by simultaneous hydrolysis and decarboxylation.

According to yet another preferred embodiment, present invention provides a process for the preparation of intermediate of formula II starting from the compound of formula X (wherein R₇ and R_$ are selected from -COOR9, -COORQ')) which has structure of formula Xc.

The process involves decarboxylation of diester intermediate of formula Xc to give compound of formula XII which is then hydrolysed to form compound of formula VI and final conversion of acid group to nitrile group to give compound of formula II.

Generally, the process involves the reaction of compound of formula Xc with a suitable decarboxylating agent. Decarboxylation reaction can be performed in the presence of suitable solvent with or without catalyst under inert reaction conditions. The suitable solvent can be selected from water, quinoline, dimethylsulphoxide, dimethylformamide, dimethylacetamide, diphenylether, dimethyl aniline, pyridine, C_3-1o ketone, C_2-io ether, halogenated solvent, nitriles, C_2-io ester, aliphatic or aromatic hydrocarbon, C₁.₁0 alcohol, polyol 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 such as sodium hydroxide. The reaction is preferably conducted at a temperature of about 0 °C to 250 °C, preferably till reaction completion. The compound of formula XII can be isolated from the reaction mixture by cooling the reaction mass. The isolation can be carried out by the methods known in the art such as extraction with a suitable solvent followed by distillation or filtration.

The compound of formula XII can be hydrolyzed to form compound of formula VI.

Generally, the process involves the hydrolysis of compound of formula XII 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; ethers; aprotic solvents such as dimethylformamide, dimethylsulfoxide, N-methylpyrrolidinone; C_MO alcohol, nitriles, C3.10 ketones, halogenated solvents, C_2-8 esters and the like or mixture thereof. The acid intermediate of formula VI 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 VI can optionally be purified to minimize the presence of impurities as well as to increase purity of the desired intermediate.

In an alternate way, acid intermediate of formula VI can be prepared directly from diester intermediate of formula Xc without isolation of intermediate of formula XII.

Finally, the acid intermediate of formula VI is converted to novel intermediate of formula II.

Generally, the process involves the reaction of acid intermediate of formula VI with a suitable reagent at a temperature of -20 °C to 180°C for few minutes to few hours, preferably till the completion of the reaction. However, reaction temperature and other conditions can be varied depending upon the nature of compound of formula VI. The reagent employed for the reaction can be selected from the reagents known in the art that can effectively be used for converting acid group to cyano group. Preferably, the reagent employed includes urea, methylsulfonyl halides with additives or alkali metal azide with additives, which can be selected from urea or benzene sulfonamide, p-toluenesulfonic acid or phosphorus pentachloride and the like. The reaction can be carried out in the absence or presence of a suitable solvent. The solvents employed for the reaction includes but not limited to C4.10 ethers, aliphatic or aromatic hydrocarbon, nitriles, aprotic solvent such a dimethylsulfoxide, dimethylformamide, N-methylpyrrolidinone and the like or mixture thereof, solvents details are as given above. After the completion, of the reaction, intermediate of formula II can be isolated from the reaction mixture using suitable techniques such as distillation or can be proceeded as such for the further reaction. Alternatively, the acid can be converted to nitrile through corresponding amide intermediate by the methods already known in the art for the conversion.

According to yet another preferred embodiment, present invention provides a process for the preparation of intermediate of formula II starting from the compound of formula X (wherein one of R7 and Rs is -CN and other is -SO₂R₁0 wherein Rio is as defined above ) which has structure of formula Xd.

The process involves desulfonylation of compound of formula Xd to give compound of formula II. Generally, the process involves the reaction of compound of formula Xd with a suitable desulfonylating agent at a suitable temperature for few minutes to few hours, preferably till the completion of the reaction. However, reaction temperature and other conditions can be varied depending upon the nature of desulfonylating agent employed. The desulfonylating agent employed for the reaction can be selected from the reagents known in the art that can be used effectively for the purpose of removal of sulfonyl group. The desulfonylation reaction can be carried out in the presence of transition metal catalyst such as Raney nickel and others; amalgams such as sodium amalgam, aluminium amalgam, zinc amalgam and the like. The presence or absence of solvent in the reaction mixture is not critical. The solvents employed for the reaction includes but not limited to water, Ci-io alcohols, C_4-io ethers, aliphatic or aromatic solvent, C_2-io esters, halogenated solvents, C3-io ketone, nitriles, aprotic solvents such as dimethylsulfoxide, N,N-dimethylformamide, dimethylacetamide, N- methylpyrrolidinone and the like or mixture thereof. After completion of the reaction, intermediate of formula II can be isolated from the reaction mixture or can be proceeded as such for the further reaction.

According to yet another preferred embodiment, present invention provides a process for the preparation of intermediate of formula II starting from the compound of formula X (wherein one of R7 and Rg is— COOR ' and other is—SO₂R₁₀ wherein Rio and R ' are as defined above ) which has structure of formula Xe.

The process involves desulfonylation of compound of formula Xe to give ester intermediate of formula XII which is then converted to compound of formula II by hydrolysis followed by cyanation reaction. Generally, the process involves the reaction of compound of formula Xe with a suitable desulfonylating agent at a suitable temperature for few minutes to few hours, preferably till the completion of the reaction. However, reaction temperature and other conditions can be varied depending upon the nature of desulfonylating agent employed. The desulfonylating agent employed for the reaction can be selected from the reagents known in the art that can be used effectively for the purpose of removal of sulfonyl group. The desulfonylation reaction can be carried out in the presence of transition metal catalyst such as Raney nickel and others; amalgams such as sodium amalgam, aluminum amalgam, zinc amalgam and the like. The reaction can be advantageously carried out in the presence of a suitable solvent. The solvents employed for the reaction includes but not limited to water, Q-io ethers, C_2-io esters, CM_O alcohols, nitriles, C_3-io ketones, halogenated solvents, aliphatic or aromatic hydrocarbon, aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide and the like or mixture thereof. After completion of the reaction, intermediate of formula XII can be isolated from the reaction mixture or can be proceded as such for the further reaction. The isolated intermediate of formula XII can be, if desired, 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 XII can be further converted to cyano intermediate of formula II by the process as already described in the present invention by the optional isolation of intermediate of formula VI. The isolated intermediate of formula II prepared by any of the above method, 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 Π (including (R)(R) or (S)(S) or (R)(S) or (S)(R) isomers or mixture of two or more in any proportion) can be prepared by from corresponding isomer of intermediate of formula X. Chiral isomer of intermediate of formula II can be prepared by employing chitral synthesis or performing resolution at the last stage. Alternatively, chiral isomer of intermediate of formula II can be prepared by employing resolution at the intermediate stage by following the methods described by the present invention.

Similarly, acid intermediate of formula VI (including (R)(R) or (S)(S) or (R)(S) or (S)(R) isomers or mixture of two or more in any proportion) can be converted to corresponding isomer of intermediate of formula II by employing the method as described above.

According to another embodiment, present invention provides a process for the preparation of compound of formula of compound of formula II (wherein R_/ is -OR₂ group),

Formula Ila wherein R? is as defined above

from a compound of formula lib, another variant of compound of formula II (wherein Rj is halo)

Formula lib

wherein Xis as defined above

Generally, the process involves the reaction of compound of formula lib with a suitable reagent that can displace halo group with OR₂ at a temperature of -20 °C to 250°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 hydroxy group. Specifically, the reagent includes but not limited to alkali or alkaline metal alkoxide, aryloxide, aralkoxide such as, sodium methoxide, sodium benzyloxide and the like. The reaction can be carried out in a solvent that includes water, aliphatic or aromatic hydrocarbon, C .10 ethers, nitriles, C_2-io esters, C3_io ketones, halogenated solvents, aprotic solvents such as dimethylsulfoxide, N.N-dimethylformamide and the like or mixture thereof. After the completion of the reaction, the compound of formula Ila can be isolated from the reaction mixture by using any conventional technique known in the art. Compound of formula Ha is the proceeded to give compound of formula I, preferably tapentadol by using the process as described in the present invention.

According to another aspect, present invention provides a process for the preparation of compound of formula X by the reaction of compound of formula XIII,

Formula XIII

where in Ri, Re and R are as defined above

using a suitable methylating agent.

Generally, the process involves the reaction of compound of formula XIII with a suitable reagent, which is capable of incorporating methyl group, in a suitable solvent at a temperature of 0°C to room temperature (RT) 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 XIII using a reagent selected from methyl halide such as methyl iodide, methyl chloride, methyl bromide; dimethyl sulfate; dimethyl carbonate, methyl phosphate such as trimethyl phosphate, methyl sulfonates and the like. The solvent employed for the reaction can be aqueous or non aqueous and is chosen on the basis of the reagent employed, preferably suitable solvent includes amide solvents such as dimethylformamide; C4-10 ether such as tetrahydrofuran; aprotic solvents such as dimethylsulphoxide, N-methylpyrrolidinone; nitriles such as acetonitrile; aliphatic or aromatic hydrocarbon such as toluene, heptane 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, triethylamine, and the like. Inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, hydride and alkoxide thereof, preferably base is selected from potassium carbonate and the like. The compound of formula X can be isolated from the reaction mixture by using any conventional technique known in the art such as extraction with water immiscible solvent followed by removal of solvent. The compound of formula X can be optionally purified to enhance the purity of the intermediate as well as to minimize the presence of impurities.

Starting compound of formula XIII can be prepared by any method known in the art. Specifically the compound of XIII can be prepared by the method described herein for the reference. Specifically, compound of formula XIII can be prepared by either of two processes as described in the following scheme.

XVII xv

wherein Rj, R7, Rs are as defined above; and LG is any leaving group selected from halo such as chloro, bromo, iodo, fluoro; -OCOR₂, -OCSR2, -SO2R2, -ONO2 and the like; wherein R2 is as defined above

According to one way, compound of formula XIII can be prepared by the reaction of compound of compound of formula XIV with compound of formula XV to give intermediate of formula XVI followed by ethylation reaction.

Generally, the process involves the condensation reaction in the presence of suitable reagent at a temperature of -80 °C to 150 °C for few minutes to few hours. Preferably, reaction can be carried at a temperature of -50 °C to 120°C till the completion of the reaction. Suitable reagent employed for the reaction include but not limited to l,8-diazabicyclo[5.4.0]undec-7-ene, ammonium chloride, ammonium acetate, carboxylic acid salts of secondary amines or phosphate salts like diammonium hydrogen phosphate and the like. The reaction can be carried out in the presence or absence of solvent provided they have no critical impact on other functionalities. Suitable solvent includes water; aliphatic or aromatic hydrocarbon, C_4-io ethers, C_2-io esters, nitrileSjCi.to alcohols, aprotic solvent such as dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone; C_3-1o ketones, halogenated solvents, and the like or mixture thereof. The compound of formula XVI thus formed can be isolated from the reaction mixture or can be proceeded to further ethylation reaction as such. Preferably compound of formula XVI can be isolated from the reaction mixture by the creating biphasic system with addition of water and water immiscible solvent followed by layer seperation. Organic layer can be optionally washed with water, or a suitable base. Resulting product can be isolated from the organic layer using suitable techniques such as distillation, evaporation and the like.

The compound of formula XVI can be treated with suitable ethyl metal or ethyl metal halide at a temperature of -50°C to 80°C for few minutes to few hours, preferably reaction can be carried till the completion of the reaction. Ethyl metal halide employed for the reaction can be selected from the reagent known in the art, preferably includes ethyl magnesium halide; ethyl aluminium halides; with or without additives. Ethyl metal includes ethyl lithium, ethyl sodium, diethyl magnesium, triethyl aluminium, diethyl zinc and the like. Suitable solvent includes Gno ether such as tetrahydrofuran; aliphatic or aromatic hydrocarbons, halogenated solvent, nitriles, C_3-io ketones, C_2-io esters, aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, N- methylpyrrolidinone and the like or mixture thereof. After the completion of the reaction, reaction mixture can be quenched, whenever required, with a suitable quenching agent such as ammonium chloride and the like. The compound of formula XIII thus formed can be isolated from the reaction mixture by suitable techniques such as extraction with a solvent followed by removal of solvent using techniques such as distillation or evaporation and the like or can be proceeded to further reaction as such.

According to another alternate way, compound of formula XIII can be prepared by the reaction of compound of formula XVII with compound of formula XV.

Generally, the process involves the condensation reaction in the presence of condensing agent at a temperature of -30 °C to 200°C for few minutes to few hours, preferably till the completion of the reaction. Suitable condensing agent employed can be selected from organic base which includes trialkylamine such as triethylamine; diisopropyl ethylamine and the like; inorganic base which includes alkali or alkalline metal hydroxide, hydride, carbonates, bicarbonates and alkoxide thereof; l,8-diazabicyclo[5.4.0]undec-7-ene. The reaction can be carried out in the presence or absence of solvent because they have no critical impact on the reaction. Suitable solvent includes water, C_4-io ethers, aliphatic or aromatic hydrocarbons, Ci.io alcohols, C_2-i₀ ethers, halogenated solvents, aprotic solvents such as dimethylsulfoxide, dimethylformamide, nitriles, C_3-io ketones, ionic liquids and the like or mixture thereof. After the completion of the reaction, the compound of formula XIII thus formed can be isolated from the reaction mixture by suitable techniques such as extraction with a solvent followed by removal of solvent using techniques such as distillation, evaporation and the like or can be proceeded to further reaction as such. Intermediate compound of formula XIII thus prepared can optionally be purified to enhance the purity.

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 subgroups, 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-dimethylaminopropane 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 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-6 alcohols, aliphatic C₃_6 ketones, aliphatic or aromatic hydrocarbons, C_2-io esters, C_3-6 ethers, nitrile, a halogenated solvents, aprotic solvents such as N,N- dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidinone, 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-dimethylaminopropane derivatives of formula I, preferably tapentadol. Main advantage of the present invention is that it yield tapentadol hydrochloride with high enantiomeric excess, more than 98 %, preferably more than 99 % ee, more preferably 100 % ee. Further, the present invention also provides novel intermediates, which are useful in the preparation of the tapentadol and its pharmaceutically salts thereof.

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

Example 1: Preparation of 2-cyano-3-(3-methoxy-phenyI)-pentanoic acid ethyl ester

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

l,8-Diazabicyclo[5.4.0]undec-7-ene (22 g, 0.15 mol) was added to a mixture of m-anisaldehyde (200 g, 1.47 mol) and ethylcyanoacetate (166 g, 1.47 mol) at ambient temperature. The reaction mixture was stirred for 6 hours at about 50 to 60 °C. The reaction mixture was cooled to RT, followed by addition of dichloromethane (2.0 L) and water (1.0 L). Thereafter, layers were separated. The organic layer was washed with water (2 x 500 ml), 10% sodium bicarbonate (1 x 400ml) and water (1 x 400ml) sequentially. The resulting organic layer was dried over anhydrous sodium sulfate and solvent was distilled off to give 345 g of title compound.

Ή-NMR (CDC1₃): 8.23-(lH,s, CffC); 7.35-(4H, m, ArH); 4.4-(2H,q, OCH₂); 3.88 -(3H, s, OCH₃); 1.40-(3H, t, CH₃CH₂)

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

To a mixture of 2-cyano-3-(3-methoxy-phenyl)-acrylic acid ethyl ester (50 g, 0.22 mol) in dry tetrahydrofuran (250 ml) under nitrogen at about -10 to -15 °C, tetrahydrofuran solution of ethyl magnesium bromide (180ml, 0.54 mol) was added and reaction mass was stirred for 1 hour at same temperature. Reaction mixture was further stirred at 15 to 25 °C till completion of reaction and then quenched with saturated aqueous solution of ammonium chloride (500 ml) at 0 to 5 °C followed by extraction with isopropyl ether (300 ml). The organic layer was washed with water (100 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off to give 56.5 g of title compound.

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

Step I: Preparation of 2-(3-methoxy-benzylidene)-malononitrile l,8-Diazabicyclo[5.4.0]undec-7-ene (1.1 lg, 0.01 mol) was added to a stirred mixture of m- anisaldehyde (lOgm, 0.07 mol) and malononitrile (5.34 g, 0.08 mol) at RT and then heated to temperature of 50-60 °C. Reaction mixture 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 layer separation. The organic layer was washed with water (2 x 10ml), 10 % sodium hydrogen carbonate (1 x 10ml) and water (1 x 20ml) sequentially. The resulting organic layer was dried over anhydrous sodium sulfate, distilled to give 16g of the title compound.

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

To a stirred mixture of 2-(3-methoxy-benzylidene)-malononitrile (15 g, 0.08 mol) in dry tetrahydrofuran (60 ml) under nitrogen at -10° to -15°C, a solution of ethyl magnesium bromide ( 54 ml, 0.16 mol) in tetrahydrofuran was added and stirred for 1 hour. Reaction mixture was further stirred at 15-25 °C till completion of reaction (monitored by TLC). After 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.

Ή-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)

By using method similar to examples 1 & 2, following compounds were prepared,

2-[l-(3-Methoxy-phenyl)-propyl]-malonic acid diethyl ester was prepared starting from meta- anisaldehyde and malonic acid diethyl ester

2- Toluene-4-sulfonyl-3-(3-methoxy-phenyl)-pentanenitrile was prepared starting from meta- anisaldehyde and (toluene-4-sulfonyl)-acetonitrile

3- (3-methoxy-phenyl)-2-(toluene-4-sulfonyl)-pentanoic acid ethyl ester was prepared starting from meta-anisaldehyde and (toluene-4-sulfonyl)-acetic acid ethyl ester

Example 3: Preparation of 2-cyano-3-(3-methoxy-phenyI)-pentanoic acid ethyl ester

To a solution of ethyl cyanoacetate (0.1 g, 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 (0.6 ml) 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 of the title compound. Example 4: Preparation of 3-(3-methoxy-phenyl)-2-(toluene-4-sulfonyl)-pentanoic acid ethyl ester

To a mixture of (toluene-4-sulfonyl)-acetic acid ethyl ester (4.23 g, 0.02 mol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (2.66 g, 0.02 mol), l-(l-bromo-propyl)-3-methoxy-benzene (4 g, 0.02 mol) was added at RT and reaction mixture was stirred at 25 °C for 3 hours. After completion of the reaction, demineralised water (5 ml) was added to the reaction mixture followed by extraction with isopropyl ether (2 x 10 ml). Layers were separated and isopropyl ether layer was washed with demineralised water. Organic layer was dried over sodium sulphate and distilled to give 3.54 g of the title compound.

Example 5: Preparation of 3-(3-methoxy-phenyl)-2-(toluene-4-sulfonyl)-pentanenitrile

To a mixture of (toluene-4-sulfonyl)-acetonitrile (3.4 g, 0.02 mol) and l,8-diazabicyclo[5.4.0]undec-7- ene (2.66 g, 0.02 mol), l-(l-bromo-propyl)-3-methoxy-benzene (4 g, 0.02 mol) was added and stirred at 25 °C for 3 hours. After completion of the reaction, demineralised water (5 ml) was added to the reaction mixture and extracted with isopropyl ether (2 x 10 ml). Layers were separated and isopropyl ether layer was washed with demineralised water. Organic layer was dried over sodium sulphate and distilled to give 3.6 g of the title compound.

By using method similar to examples 3, 4 & 5, following compounds were prepared,

2-[l-(3-Methoxy-phenyl)-propyl]-malononitrile was prepared from l-(l-bromo-propyl)-3-methoxy- benzene and malononitrile

2-[l-(3-Methoxy-phenyl)-propyl]-malonic acid diethyl ester from l-(l-bromo-propyl)-3-methoxy- benzene and malonic acid diethyl ester

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

To a solution of 2-cyano-3-(3-methoxy-phenyl)-pentanoic acid ethyl ester (322 g, 1.23 mol) in dimethylsulfoxide (966ml), potassium carbonate (681 g, 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.

Ή-NMR (CDC1₃): 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.) Example 7: Preparation of 2-[l-(3-methoxy-phenyl)-propylJ-2-methyl-malononitrile

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 (150 ml). 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. Ή- MR (CDC1₃): 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);

Example 8: Preparation of 3-(3-methoxy-phenyl)-2-methyl-2-(toluene-4-sulfonyl)-pentanoic acid ethyl ester

Potassium carbonate (2.41 g, 0.02 mol) was added to a solution of 3-(3-methoxy-phenyl)-2-(toluene-4- sulfonyl)-pentanoic acid ethyl ester (3.41 g, 0.01 mol) in dimethylsulfoxide (15 ml) and stirred for 15 minutes at 25 °C. Methyl iodide (1.24 g, 0.01 mol) was added to the reaction mixture and stirred for 1 hour at 25 °C followed by addition of water (5 ml). Reaction mixture was extracted with isopropyl ether (3 x 10 ml) and combined organic layer was washed with demineralised water. Resulting organic layer was dried over sodium sulphate and distilled to give 2.65 g of the title compound.

Example 9: Preparation of 3-(3-methoxy-phenyl)-2-methyl-2-(toluene-4-sulfonyl)-pentanenitrile Potassium carbonate (2.42 g, 0.018 mol) was added to a solution of 3-(3-methoxy-phenyl)-2-(toluene- 4-sulfonyl)-pentanenitrile (3 g, 0.01 mol) in dimethylsulfoxide (15 ml) and stirred for 15 minutes at 25 °C. Methyl iodide (1.24 g, 0.01 mol) was added to the reaction mixture and stirred for 1 hour at 25 °C followed by addition of water (5 ml). Reaction mixture was extracted with isopropyl ether (3 x 10 ml) and the combined organic layers were washed with demineralised water. Resulting organic layer was dried over sodium sulphate and distilled to give 2.5 g of the title compound.

By using method similar to examples 6 to 9, 2-[l-(3-methoxy-phenyl)-propyl]-2-methyl-malonic acid diethyl ester was prepared from 2-[l-(3-methoxy-phenyl)-propyl]-malonic acid diethyl ester.

Example 10: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentanenitrile

Method A: To a stirred solution of 2-[l-(3-methoxy-phenyl)-propyl]-2-methyl-malononitrile (0.5 g, 0.002 mol) in toluene (2.5 ml), azobisisobutyronitrile (0.004 g) and tributyltin hydride (0.765 g, 0.003 mol) were added at RT and heated to reflux for 10 hours. Reaction mixture was cooled to ambient temperature. l,8-diazabicyclo[5.4.0]undec-7-ene ( 0.433 g, 0.003 mol) and isopropyl ether (2 ml) was added to the reaction mixture. Reaction mixture was concentrated to give a residue which was purified to give 0.15 g of the title compound. Method B:

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

To a stirred solution of 2-cyano-3-(3-methoxy-phenyl)-pentanoic acid ethyl ester (30 g, 0.12 mol) in toluene (150 ml) under nitrogen atmosphere, sodium hydride (22 g, 0.46 mol) was added and stirred for 1 hour at RT. Thereafter, methyl iodide (24.6g, 0.23 mol) was added to the reaction mixture at RT and reaction mixture was heated to about 45- 50 °C and stirred for 4 hours. Reaction mixture was quenched with water (90ml) at about 0 to 5°C and stirred for 2 hours followed by extraction with isopropyl ether (3 x 150 ml). Isopropyl ether layer was discarded. The aqueous layer was cooled to about 0 to 5 °C and acidified using concentrated hydrochloric acid till pH 1. The resulting reaction mass was again extracted with isopropyl ether (3 x 150 ml) and the organic layer was washed with water (100 ml). The resulting organic layer was dried over anhydrous sodium sulfate and solvent was distilled off to give 28 g of title compound.

Step II: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentanenitrile

To a stirred solution of 2-cyano-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (18g, 0.07 mol) in dimethylsulfoxide (72 ml), lithium chloride (12.35 g, 0.29 mol) was added at RT and heated at about 150 - 160°C for 15 hours. The reaction mixture was then cooled to room temperature followed by addition of cold water (220 ml) to the reaction mixture. Thereafter reaction mixture was extracted with isopropyl ether (3 x 150 ml). Combined organic layer was washed with water (90 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off to give 10 g of title compound.

Method C:

Step I: Preparation of 3-(3-methoxy-phenyI)-2-in ethyl-pen tanoic acid

To a stirred solution of 2-[l-(3-methoxy-phenyl)-propyl]-2-methyl-malonic acid diethyl ester (1 g, 0.003 mol) in monoethylene glycol (5 ml), sodium hydroxide powder (0.5 g, 0.01 mol) was added at RT and heated to 170-180 °C for 4 hours. After the completion of reaction, water was added (10 ml) to the reaction mixture at 50 °C and 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. Reaction mixture was extracted with isopropyl ether (3 x 5 ml). Combined isopropyl ether layer was washed with demineralised water and dried over sodium sulphate. Solvent was distilled to give 0.94 g of the title compound.

Ή-NMR (CDC1₃): 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); Step II: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentaneiiitrile

A mixture of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (2 g, 0.01 mol) and urea (0.65 g, 0.01 mol) was heated to 200 to 220 °C for 8 hours. The reaction mixture was distilled under vacuum to give 0.68 g of the title compound.

Method D: To a solution of 3-(3-methoxy-phenyl)-2-methyl-2-(toluene-4-sulfonyl)-pentanenitrile (1 g, 0.003 mol) in methanol (10 ml), sodium amalgam (4 g, 5%) was added at 25-30 °C and mixture was stirred for 5 hours. After completion of reaction , methanol was separated from amalgam, and distilled off completely at 50-55 °C under vacuum. Resulting residue was dissolved in toluene (5 ml) and washed with 5 % sodium bicarbonate solution (2 ml) and then with demineralised water (2 ml). Toluene was distilled from the reaction mixture to give 0.3 g of the title compound.

Method E:

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

To a stirred solution of 3-(3-methoxy-phenyl)-2-methyl-2-(toluene-4-sulfonyl)-pentanoic acid ethyl ester (1 g, 0.002 mol) in ethanol (10 ml), sodium amalgam (3.5 g, 5 %) was added at 25-30 °C and mixture was stirred for 15 hours. After completion of reaction , ethanol was separated from amalgam, and distilled off completely at 50-55 °C under vacuum. Resulting residue was dissolved in toluene (5 ml) and washed with sodium bicarbonate solution (2 ml) and finally with demineralised water (2 ml). Toluene was distilled to give 0.28 g of the title compound.

Step Π: Preparation of 3-(3-methoxy-phenyl)-2-methyI-pentanenitrile

To a solution of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid ethyl ester (0.53 g, 0.002 mol) in toluene (2.5 ml), sodamide (0.166 g, 0.004 mol) was added at RT and refluxed for 4 hours. Reaction mixture was cooled to ambient temperature. Phosphorus oxychloride (0.325 g, 0.002 mol) was added to the reaction mixture and mixture was refluxed. After completion of the reaction, reaction mixture was cooled to ambient temperature and washed with cold water (2.5 ml). Layers were separated and organic layer was dried, distilled off to give 0.15 g of the title compound.

3-(3-Methoxy-phenyl)-2-methyl-pentanenitrile prepared by example 10 was characterized by Ή- NMR and display following peaks:

'H-NMR (CDC1₃): 7.0 (4H, m, ArH); 3.8, 3.79 (3H, s each, OCH₃ of both diast.);

2.94, 2.75 (1H, m, each CHCN of both diast.); 2.57 (1H, m, each, CHAr of both diast.); 2.1,1.73 (2H, m,each CH₃CH₂ of both diast); 1.19,1.13 (3H, d each, CH₃CH of both diast.); 0.86,0.77 (3H, t, each,CH₃CH₂ of both diast.) Example 11: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentylamine

To a stirred solution of 3-(3-methoxy-phenyl)-2-methyl-pentanenitrile (5 g, 0.03 mol) in toluene (25 ml) under nitrogen atmosphere, borane-dimethylsulfide (5 ml, 0.05 mol) was added at about 25 - 30 °C. The reaction mixture was heated at about 75-80°C for 4 hours and then cooled to about 0 °C. Methanol (15 ml) was added to the reaction mixture and stirred for 1 hour. The solvents were distilled off. Isopropyl ether (25 ml) and aqueous hydrochloric acid (30 ml) was added to the resulting residue. The reaction mixture was stirred for 2 hours and the layers were separated. The aqueous layer was basified with 10% sodium carbonate solution (13 ml) and extracted with dichloromethane (50 ml). The organic layer was washed with water (30 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic layer to give 5 g of title compound.

Example 12: Preparation of dibenzyl-[3-(3-methoxy-phenyl)-2-nietliyl-pentylJ-amine

To a stirred solution of 3-(3-methoxy-phenyl)-2-methyl-pentylamine (1 g, 0.01 mol) in dichloromethane (8 ml), potassium carbonate (1.67 g, 0.01 mol) and benzyl bromide (1.65 g, 0.01 mol) were added at RT and stirred for 48 hours. After the completion of reaction, layers were separated. Organic layer was washed with water (2 x 5 ml), dried and distilled to give 0.94 g of the title compound.

Example 13: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentylamine

A mixture of dibenzyl-[3-(3-methoxy-phenyl)-2-methyl-pentyl]-amine (0.8 g, 0.002 mol), toluene (10 ml) and palladium on carbon (10 %, 0.16 g) were stirred in hydrogen atmosphere for 15 hours. Reaction mixture was filtered and solvent was distilled from filtrate to give 0.22 g of the title compound.

Example 14: Preparation of [3-(3-methoxy-phenyl)-2-metliyl-pentyl]-dimetliyl-amine

A mixture of 3-(3-methoxy-phenyl)-2-methyl-pentylamine (4.0g, 0.02 mol), 37% aqueous formaldehyde (4.7 ml, 0.06 mol) and formic acid (2.7 ml, 0.06mol) was heated at about 75-80°C for 4 hours and distilled off. The reaction mass was basified with 10% sodium carbonate solution (21 ml) and extracted with dichloromethane (40 ml). Organic layer was washed with water (30 ml), dried over anhydrous sodium sulfate and solvent was distilled off to give 3.8 g of title compound.

'H- MR (CDC1₃): 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 15: Preparation of 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)-phenol

A mixture of [3-(3-methoxy-phenyl)-2-methyl-pentyl]-dimethyl-amine (lg, 0.004 mol) and aqueous hydrobromic acid (46%, 10 ml) was heated under stirring at about 90 - 100 °C for 3 hours and cooled to about 40°C. The reaction mixture was distilled off. The resulting residue was basified with sodium carbonate solution (4.8 ml) and 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 0.8 g of title compound.

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

To a stirred solution 3-(3-methoxy-phenyl)-2-methyl-pentanenitrile (10 g, 0.05 mol) in monoethylene glycol (40 ml), sodium hydroxide powder (11.8 g, 0.30 mol) was added at RT 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 tert-butyl ether (3 x 50ml) and organic layer was washed with demineralised water. The resulting organic layer was dried over sodium sulphate and distilled to give 10.2 g of the title compound.

^!H- MR (CDC1₃): 7.0-(4H,m,ArH); 3.81,3.80-(3H, s each, OCH₃ of both dias ); 2.7-(2H, m,CHAr & CHCOOH of both diast); 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 17: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid dimethylamide Step I: Preparation of 3-(3-methoxy-phenyl)-2-methyl-pentanoyl chloride

To a stirred solution of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (14 g, 0.06 mol) in dry toluene (70 ml), thionyl chloride (9 g, 0.08 mol) was added at RT and reaction mixture was heated at 75 - 80 °C for 3 hours. Toluene was distilled off from the reaction mixture at under vacuum to give 15.2 g of the title compound.

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

A solution of sodium carbonate (20 g, 0.19 mol), water (56 ml), aqueous dimethylamine (14.23 ml, 0.13 mol) and toluene (56 ml) was stirred at 0 °C and a solution of 3-(3-methoxy-phenyl)-2-methyl- pentanoyl chloride (15.2 g, 0.06 mol) in dry toluene (56 ml) was added to the above solution at 0-5 °C. Reaction mixture was stirred at 0-5 °C for 1 hour. After completion of reaction, toluene layer was separated, washed sequentially with IN hydrochloric acid (14 ml), concentrated hydrochloric acid in 98 ml water) and then with water (140 ml). Resulting organic layer was dried over anhydrous sodium sulphate and distilled off to give 13.83 g of the title compound.

Example 18: Preparation of [3-(3-methoxy-phenyl)-2-methyl-pentyl]-dimethyl-amine

To a stirred solution of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid dimethylamide (10 g, 0.04 mol) in dry tetrahydrofuran (50 ml) under nitrogen atmosphere, borane dimethylsulfide (12 ml, 0.12 mol) was added at 20-25 °C. Reaction mass was stirred at 75-80 °C for 3 hour. Methanol (20 ml) was added to the reaction mixture at 0-5 °C and stirred for 30 minutes. Solvents were distilled off and isopropyl ether (80 ml) was added to the resulting residue followed by addition of 5% aqueous hydrochloric acid (40 ml) and water (40 ml). Layers were separated. Aqueous layer was basified with aqueous sodium carbonate and resulting product was extracted with isopropyl ether. Isopropyl ether layer was separated, dried over sodium sulphate and distilled off to give 8.69 g of the title compound.

Example 19: Preparation of 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)-phenol

A mixture of [3-(3-memoxy-phenyl)-2-memyl-pentyl]-dimethyl-amine (5 g, 0.02 mol) and aqueous hydrobromic acid (46 %, 38 ml) was heated under stirring at 100 - 105 °C for 3 hours and then cooled to 20 °C. The excess hydrobromic acid was degassed, reaction mixture was neutralized with sodium bicarbonate and the product was extracted with dichloromethane (30 ml). Dichloromethane layer was washed with water (25 ml) and dried over anhydrous sodium sulfate. Solvent was distilled off to give 3.38 g of the title compound which was stirred in ethyl acetate (5 ml) for 2 hours, filtered and dried to give 2.44 g of the title compound.

Example 20: Preparation of 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)-phenol hydrochloride Method A: To a stirred solution of 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)-phenol (0.25 g, 0.001 mol) in methanol (2 ml) isopropyl ether hydrochloride (0.45 ml, 11.7%) was added and reaction mixture was stirred for 1 hour at 25-30 °C. Thereafter, solvents were distilled off from the reaction mixture. Resulting residue was stirred in ethyl acetate (3 ml) for 2 hours, filtered and dried to give 0.22 g of the title compound.

Method B: A mixture of [3-(3-memoxy-phenyl)-2-memyl-pentyl]-dimemyl-amine (1.0 g, 0.004 mol) and aq. hydrobromic acid (46%, 8ml) was heated under stirring at 100- 105 °C for 3 hours and then cooled to 20 °C. Thereafter, reaction mixture was neutralized with sodium bicarbonate and the product was extracted with dichloromethane (30 ml). Organic layer was washed with water (2 x 5 ml) and treated with 2N-hydrochloric acid (4 ml). Resulting organic layer was washed with water (2 x 5 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off to give 0.67 g of the title compound.

Example 21: Preparation of tapentadol

To a stirred mixture of 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)-phenol (0.24 g), methyl isobutyl ketone (5 ml), D-dibenzoyl tartaric acid (0.194 g) and methanol (0.1 ml) was added at RT. The reaction mass was stirred for about 10-15 minutes at about 25 °C and filtered. Dichloromethane (5 ml) was added to the resulting residue, basified with 10% sodium carbonate solution (2.2 ml) and was stirred maintaining the pH 8.0. Organic layer was separated out and washed with demineralised water. Layers were separated. Organic layer was treated with 2N hydrochloric acid (4 ml and washed with demineralised water (2 5 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off to give title compound.

Example 22: Preparation of (R)(R)-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid

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

A solution of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (150 g, 0.675 mol) and (R)-(+)-a- methylbenzylamine (41 g, 0.338 mol) in isopropyl ether (825 ml) was heated to 70-75 °C and stirred 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 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-methyI-pentanoic acid

To the above (R), (R)-isomer (19.2 g) in methyl tertiary butyl ether (100 ml); hydrochloric acid (40 ml, 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= -18.5 (c = 1%; toluene);

Similarly, (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. 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 23: Preparation of (R)(R)-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid dimethylamide

Step I: Preparation of (R)(R)-3-(3-methoxy-phenyl)-2-methyI-pentanoyl chloride

To a stirred solution of (R)(R)-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid (7 g, 0.03 mol) in dry toluene (35 ml), thionyl chloride (4.5 g, 0.04 mol) was added to the reaction mixture and heated at 75 - 80 °C for 3 hours. Solvent was distilled off from the reaction mixture to give 7.58 g of the title compound. Step II: Preparation of (R)(R)-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid dimethylamide

A solution of sodium carbonate (10 g, 0.09 mol), water (28 ml), aqueous dimethyl amine (7.11 ml, 0.06 mol) and toluene (28 ml) was stirred at 0 °C and resulting solution was added to a solution of (R)(R)-3- (3-methoxy-phenyl)-2-methyl-pentanoyl chloride (7.58 g, 0.03 mol) in toluene (28 ml) at 0-5 °C. Reaction mixture was stirred at 0-5 °C for 1 hour. After completion of reaction, toluene- layer was separated. Toluene layer was washed with IN hydrochloric acid (56 ml), water (70 ml), dried over anhydrous sodium sulphate, and distilled off to give 7.07 g of title compound.

Similarly, (S)(S) isomer, (S)(R) and (R)(S) of 3-(3-methoxy-phenyl)-2-methyl-pentanoic acid dimethylamide were prepared starting from the corresponding isomer of 3-(3-methoxy-phenyl)-2- methyl-pentanoic acid.

Example 24: Preparation of (R)(R)-[3-(3-methoxy-phenyl)-2-methyl-pentyl]-dimethyl-amine

To a stirred solution of (R)(R)-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid dimethylamide (5 g, 0.02 moles) in dry tetrahydrofuran (25 ml) under nitrogen atmosphere, borane-dimethylsulfide (6 ml, 0.06 mol) was added at 20-25 °C and reaction mixture was stirred at 75-80 °C for 3 hours. After completion of the reaction, methanol (10 ml) was added to the reaction mixture at 0-5 °C and stirred for 30 minutes. Solvents were distilled off and resulting residue was dissolved in isopropyl ether (40 ml). Reaction mixture was washed with 5 % aqueous hydrochloric acid (20 ml) and water (20 ml). Resulting isopropyl ether layer was dried over sodium sulphate and distilled off to give 4.25 g of the title compound.

Similarly, (S)(S) isomer, (S)(R) and (R)(S) isomer of [3-(3-methoxy-phenyl)-2-methyl-pentyl]- dimethyl-amine were prepared starting from the corresponding isomer of 3-(3-methoxy-phenyl)-2- methyl-pentanoic acid dimethylamide.

Example 25: Preparation of (R),(R)-3-(3-dimethylamino-l-ethyl-2-methyl-propyl)-phenoI (tapentadol)

A mixture of (R), (R)-[3-(3-memoxy-phenyl)-2-methyl-pentyl]-dimemyl-amine (4 g, 0.02 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 of title compound. The resulting product was stirred in ethyl acetate (5 ml) for 2 hours, filtered and dried to give 2.63 g of title compound. Similarly, (S) (S) isomer, (S) (R) and (R) (S) isomer of 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)- phenol were prepared starting from the corresponding isomer of [3-(3-methoxy-phenyl)-2-methyl- pentyl] -dimethyl-amine.

Example 26: Preparation of tapentadol hydrochloride

Method A: To a stirred solution of tapentadol (0.25 g, 0.001 mol) in methanol (2 ml), isopropyl ether hydrochloride (0.45 ml, 11.7%) was added at RT 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 of the title compound.

Method B: A mixture of (R),(R)-[3-(3-memoxy-phenyl)-2-memyl-pentyl]-dimemyl-amine (l.Og, 0.004 mol) and aqueous hydrobromic acid (46%, 8ml) was heated under stirring at 100-05°C for 3 hours and cooled to 20°C. Thereafter reaction mixture was neutralized with sodium bicarbonate and extracted with dichloromethane (30 ml). Organic layer was washed with water (2 x 5 ml) and treated with 2N-hydrochloric acid (4 ml). Resulting organic layer was washed with water (2 5 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off to give 0.67 g of the title compound (0.67g, 61%).

[a]_D ^RT= -27.6 (c = 0.97% ; methanol) and melting point: 168-170 °C

Similarly, hydrochloride salt of (S) (S) isomer, (S) (R) and (R) (S) isomer of 3-(3-dimethylamino-l- ethyl-2-methyl-propyl)-phenol were prepared starting from the corresponding free base which may be used as reference standard as well as reference marker (as free base or their salt) to detect the presence of these isomeric impurities in tapentadol or its hydrochloride.

Claims

WE CLAIM:

1. A process for the preparation of l-phenyl-3-dimethylaminopropane derivatives of formula I,

Formula I

or its isomers, enantiomers, diastereomers, racemates, solvates, hydrates or pharmaceutically acceptable salts thereof starting from cyano intermediate of formula II,

Formula II

wherein Rj can be selected from -OR₂, halo, -CH₂OR₂, -SR₂, -SOR₂, -S0₂R₂, -SO₃H, -N0₂, -NR₂R₂ ', -CONR₂R₂', carbox lic esters, sulfonate esters or phosphate esters; R₂ and R₂ ' can be same or different and can be selected from hydrogen, alky I, aryl, aralkyl, heteroaryl, -COR₂ ", -POs(R₂ ")₂ wherein R₂ ' ' can be selected from alkyl, aryl, aralkyl, heteroaryl and the like

2. The process according to claim 1, wherein in compound of formula II is (R),(R) or (S),(S)- or (R),(S)- or (S)(R)-isomer of compound of formula II or mixture of two or more in any proportion.

3. 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 the cyano intermediate of formula II using a suitable reducing agent to form an intermediate of fo

Formula III

wherein Ri is as defined above

b). reacting the intermediate of formula III with a suitable methylating agent to form intermediate of formula IV; and

Formula IV

wherein Rj is as defined above

c). converting compound of formula IV into l-phenyl-3-dimethylaminopropane derivatives of formula I.

4. The process according to claim 3, wherein in step a) reducing agent is selected from borane, borane- Lewis base complex; borane tetrahydrofuran (BH₃.THF); borane complex with substituted amine (BH3.NR R R ^"", wherein R , R and R are alkyl, aryl, aralkyl, or alkaryl and the like), borane complex with substituted phosphine (BH₃.PR R R , wherein R , R and R are alkyl, aryl, aralkyl, or alkaryl and the like), borane dimethylsulfide; metal hydride such as lithium aluminium hydride; alkali or alkaline metal borohydride such as potassium borohydride, sodium borohydride; with or without additives; or Red-Al and the like; 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.

5. The process according to claim 3, wherein in step b) methylating agent is selected from formaldehyde in combination with formic acid or metal hydride or Pd/C with hydrogen pressure, methyl halide such as methyl iodide, methyl chloride, methyl bromide; dimethyl sulfate; methyl sulfates, dimethyl carbonate, trimethyl phosphate, methyl phosphates and the like.

6. The process according to claim 3, wherein compound of formula III can be optionally converted to intermediate of formula

Formula V

wherein R3 and R4 are nitrogen protecting group, can be same or different and independently can be selected from alkyl, aryl, aralkyl, alkaryl, -SO₂R₂, -S0₂Ar, -COR₂ ", -P0₃(R₂ ")₂ (wherein R₂ and R₂ " are as defined above); R3 and R4 can be combined to form a five membered heterocyclic ring or five membered heterocyclic ring fused with six membered ring; provided both R3 and R4 are not methyl group

by treating with a suitable reagent; followed by deprotecting compound of formula V using a suitable deprotecting reagent to form intermediate of formula III.

7. The process according to claim 6, wherein suitable reagent is selected from formaldehyde with formic acid; alkyl halide, aryl halide, aralkyl halide, alkyl sulfate, aryl sulfate, aralkyl sulfate, alkyl phosphates, aryl phosphates, aralkyl phosphates, sulfonyl halides, acyl halide, phosphoryl halide, tert-butyldicarbonate; alkyl or arylhaloformate such as benzylchloroformate, ethylchloroformate and the like; and suitable deprotecting reagent is selected from borane compounds like borane trihalide; beryllium compounds such as beryllium 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; organic acid including carboxylic acid such as acetic acid; inorganic acid; organic or inorganic base; hydrogenolysis using a catalyst including transition metals with or without support (carbon) such as palladium, platinum, nickel and the like.

8. A process for the preparation of l-phenyl-3-dimethylaminopropane derivatives of formula I or pharmaceutically acceptable salts thereof, comprising the steps of:

a) , hydrolyzing the cyano intermediate of formula II using a suitable reagent to form an acid intermediate of formula VI,

Formula VI

wherein Ri is as defined above

c) . reacting acid intermediate of formula VI or reactive derivative thereof with amine of formula

VII,

mr^Rs

Re Formula VII

wherein R5 and R can be same or different and independently can be selected from hydrogen, alkyl, aryl, aralkyl, alkaryl, -S0₂R₂, -S0₂Ar, -COR₂ ", -P0₃(R₂ ")₂ wherein R₂ and_t R₂" are as defined above

in the presence of suitable base to form amide intermediate of formula VIII,

Formula VIII

wherein R^R^and Re are as defined above

d). reducing the amide intermediate of formula VIII with a suitable reducing agent to form compound of formula IX; and

Formula IX

wherein Rj_ R^and Re are as defined above e). converting compound of formula EX to l-phenyl-3-dimethylaminopropane derivatives of formula I.

9. The process according to claim 8, wherein in step a) suitable reagent is selected from acid which 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 which includes alkali or alkaline metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like (with or without additives);

10. The process according to claim 8, wherein in step b) reactive derivative is selected from acid halides, organic acid anhydrides, mixed acid anhydride, cyclic carboxy-anhydrides, active amides or esters, triazole such as benzotriazole and the like.

11. The process according to claim 8, wherein compound of formula VI used is (R),(R)- or (S),(S)- or (R),(S)- or (S)(R)-isomer of compound of formula VI or mixture of two or more in any proportion.

12. The process according to claim 8, wherein in step c) suitable base is selected from organic base such as trialkylamines, substituted amines and the like; and inorganic base such as alkali or alkaline metal hydroxide, alkoxide, hydride, carbonate, bicarbonate thereof.

13. The process according to claim 8, wherein in step d) reducing agent is selected from borane, borane -Lewis base complex; borane tetrahydrofuran (BH₃.THF); borane complex with substituted amine (BH₃.NR R R , wherein R , R and R are alkyl, aryl, aralkyl, or alkaryl and the like), borane complex with substituted phosphine (BH₃.PR R R , wherein R , R- and R are alkyl, aryl, aralkyl, or alkaryl and the like), borane dimethylsulfide; metal hydride such as lithium aluminium hydride; alkali or alkaline metal borohydride such as potassium borohydride, sodium borohydride; with or without additives; or Red-Al and the like; 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.

14. The process according to any preceding claim, wherein l-phenyl-3-dimethylaminopropane derivatives of formula I is tapentadol of formula la,

Formula la

or its pharmaceutically acceptable salts.

15. The process according to claim 1, wherein cyano intermediate of formula II is prepared starting from intermediate of formula X.

Formula X

wherein Rj is as defined above; R7 , Rs can be same or different and can be independently selected from -CN, -COOR9, -COOR9 ', -S0₂Rio: provided both R₇ andR_s can not be -SO2R10; R9, Rg 'andRjo can be same or different and can be selected independently from alkyl, aryl, heteroaryl, aralkyl, alkaryl group

16. A compound of

Formula Π wherein Rj is as defined above

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.

17. A compound of

Formula III

wherein Rj is as defined above

18. An acid intermediate of formula VI,

Formula VI

wherein is as defined above

19. An amide intermediate of formula VIII,

Formula VIII

wherein Rj_, R_$and Re are as defined above

20. A compound of

Formula X

wherein Rj_? Rjand Rs <*^re °s defined above