WO2009019719A2

WO2009019719A2 - Process for the preparation of 3-aryloxy-3-arylpropanamines

Info

Publication number: WO2009019719A2
Application number: PCT/IN2008/000490
Authority: WO
Inventors: Venkateswaran Srinivasan Chidambaram; Perminder Singh Johar; Lalith Wadhwa
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2007-08-09
Filing date: 2008-08-07
Publication date: 2009-02-12
Also published as: WO2009019719A3

Abstract

The present invention provides a process for the preparation of 3-aryloxy-3-aryl?ropanamine derivatives. Particularly the present invention provides a process for the preparation of duloxetine and pharmaceutically acid addition salts thereof specifically, duloxetine hydrochloride of formula (I), using 3-O-protected propanolamine derivatives. The invention also aims at providing a process for the preparation of highly pure duloxetine hydrochloride of formula (I) from duloxetine free base via its acid addition salts The invention further aims at providing a process for the purification of duloxetine hydrochloride, wherein the level of unwanted R-enantiomer is reduced to nearly 0%.

Description

PROCESS FOR THE PREPARATION OF 3-ARYLOXY-3-ARYLPROPANAMINES

FIELD OF THE INVENTION

The present invention provides an industrially advantageous process for the preparation of 3- aryloxy-3-arylpropanamine derivatives. Particularly, the present invention provides a process for preparing duloxetine and pharmaceutically acceptable salts thereof, specifically duloxetine hydrochloride of formula I,

-HCl Formula I

The present invention also provides a novel and efficient process for the preparation of N,N- dimethyl-3-(l-naphthenyloxy)-3-(2-thienyl) propanamine or acid addition salts thereof involving 3- O-protected propanolamine derivative, useful synthetic intermediate.

The present invention further provides a process for the preparation of highly pure duloxetine pharmaceutically acceptable salt such as duloxetine hydrochloride and provides a process for the purification of duloxetine hydrochloride for the removal of R-enantiomer impurity. BACKGROUND OF THE INVENTON

3-Aryloxy-3-arylpropanamines are known to be the potent inhibitors of both serotonin and norepinephrine uptake and are useful for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin and norepinephrine in mammals including obesity, depression, alcoholism, pain, loss of memory, anxiety, smoking, and the like. One of the 3-Aryloxy- 3-arylpropanamine derivative, duloxetine hydrochloride of formula I is marketed as 'cymbalta' by Eli Lilly and is chemically known as (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride.

-HCl Formula I

Duloxetine has been found to have application in the treatment of stress urinary incontinence (SUI), depression and pain management. It works by increasing the amounts of serotonin and norepinephrine, natural substances in the brain that help maintain mental balance and stop the movement of pain signals in the brain. Duloxetine and pharmaceutically acceptable acid addition salts thereof were first disclosed in US patent 5,023,269. This patent discloses a process for the preparation of duloxetine which comprises converting 2-acetylthiophene to 3-dimethylamino-l-(2-thienyl)-l-propanone hydrochloride under Mannich reaction conditions, reducing the same to corresponding alcohol, and converting it to N,N- dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine by reacting with 1-fluoronaphthalene in the presence of sodium hydride. N,iV-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, a key intermediate for duloxetine, is isolated as oxalate salt and then converted to the carbamate intermediate by reaction with phenyl chloroformate or trichloroethyl chloroformate. The carbamate intermediate is hydrolyzed with base to obtain duloxetine free base. This patent further exemplifies the isolation of duloxetine base as its oxalate salt and crystallization from ethyl acetate and methanol to yield duloxetine oxalate. Patent is completely silent about the chiral purity of the final product.

Paraformaldehyde NaBH₄

Dimethylamine

NaOH

hydrochloride .HCl NaH Dimethylacetamide 1 -fluoronaphlthalene

US patent 5,362,886 discloses a stereo specific process for the preparation of duloxetine hydrochloride, wherein (S)-(-)-iV^r,iV-dimethyl-3-hydroxy-3-(2-thienyl)propanamine is reacted with 1- fluoronaphthalene in the presence of sodium hydride, a potassium compound preferably potassium benzoate or potassium acetate, in an organic solvent to form (S)-(+)-N,JV-dimethyl-3-(l- naphthalenyloxy)-3-(2-thienyl)propanarnine, a key intermediate that is isolated as its phosphoric acid salt. The patent further discloses the demethylation of the above intermediate to form duloxetine base which is further converted to its hydrochloride salt. It is disclosed that duloxetine hydrochloride prepared by the above process is found to contain R-enantiomer of following formula,

as an impurity in more than 0.35% even after recrystallization. US patent 6,541,668 discloses a process for the preparation of duloxetine or acid addition salts thereof by the reaction of alkoxide of 7V,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine with 1- fluoronaphthalene in the presence of potassium tertiarybutoxide and l,3-dimethyl-2- imadazolidinone or JV-methylpyrrolidinone as solvent to form iV,N-dimethyl-3-(l-naphthalenyloxy)- 3-(2-thienyl)propanamine, a key intermediate for duloxetine which is then demethylated to form duloxetine or acid addition salts thereof.

US application 2006/0205956 discloses a process for the preparation of duloxetine or acid addition salts thereof by the O-alkylation of iV,iV^"-dimethyl-3 -hydroxy -3-(2-thienyl)propanamine with 1- fluoronaphthalene in presence of a weaker base such as metal carbonates or hydroxides and phase transfer catalyst to form DΝT which is then demethylated to give duloxetine or acid addition salts thereof.

US application 2007/0167636 discloses a process for the preparation of (S)-duloxetine by the arylation of (S)-N-methyl-3-hydroxy-3-(2-thienyl)propanamine with 1-fluoronaphthalene in presence of potassium hydroxide in presence of organic solvent or mixture of organic solvent such as dimethylsulfoxide and toluene.

US application 2007/0238883 discloses the preparation of (S)-duloxetine or pharmaceutically acceptable salts thereof by the condensation of (S)-iV,iV-dimethyl-3-hydroxy-3-(2-thienyl) propanamine with a base such as metal hydroxide, metal alkoxides, and a halonaphthalene in a polar aprotic solvent without using any phase transfer catalyst to give (S)-DΝT which is then converted to (S)-duloxetine or pharmaceutically acceptable salts thereof.

US application 2006/0276660 discloses a process for the purification of duloxetine hydrochloride by crystallizing duloxetine hydrochloride from solvent selected from C_3-8 ketone, C_3-8 esters, C_2-8 ethers, C_2-8 alcohols, and mixture thereof with water to reduce impurities namely R-enantiomer and (+)-iV-methyl-3-(l-naphthalenyloxy)-3-(3-thienyl)propanamine (DLX-ISO₃). However over all yield during purification has reduced up to 7-8%, which is very low and may leads to increase in cost and hence making the process unattractive for commercial scale.

PCT publication WO 2006/045255 discloses the preparation of (S)-duloxetine or pharmaceutically acceptable salts thereof by the reaction of racemic ΛζiV-dimethyl-3-hydroxy-3-(2- thienyl)propanamine with 1-fluoronaphthalene in a solution of dimethylsulfoxide at 80 to 15O⁰C in the presence of a base selected from alkali metal carbonates, hydroxides or alcoholates to give racemic DNT followed by resolution with optically active acid and demethylation with alkyl chloroformate to give (S)-duloxetine or pharmaceutically acceptable salts thereof. PCT publication WO 2007/96707 discloses the preparation of duloxetine by the condensation of (S)- N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine with 1-fluoronaphthalene in the presence of at least one of alkaline metal hydroxide or alkoxide in dimethylsulfoxide or its co-solvent mixture, optionally with sodium sulfate or potassium carbonate to give (S)-DNT intermediate which is then reacted with a chloro formate in presence of acid scavenger in a solvent to form duloxetine.

PCT publication WO 2007/077580 discloses a process for the preparation of duloxetine hydrochloride which comprises reacting 2-acetylthiophene with dimethylamine hydrochloride followed by purifying and reducing the resulting ketone intermediate to N,N-dimethyl-3-hydroxy-3- (2-thienyl)propanamine. The same compound is resolved with a chiral acid, purified and treated with weak inorganic base. The compound so formed is reacted with 1-fluoronaphthalene in the presence of an alkaline base, and in situ treatment with oxalic acid to obtain duloxetine oxalate and converting the same into duloxetine hydrochloride. Conversion of duloxetine oxalate salt to hydrochloride salt is effected using ethyl acetate hydrochloride, methanolic hydrochloride, isopropyl alcohol hydrochloride, in a suitable solvent like alcohol or ester. The patent application also discloses a process for the purification of duloxetine hydrochloride from solvents including ester, alcohol, or mixture thereof.

The drawbacks of above processes involve the use of sodium hydride which react with water, liberating flammable hydrogen or use of alkoxides which require special handling and safety conditions, which makes the process unattractive from commercial point of view. Also the use of l,3-dimethyl-2-imadazolidinone or N-methylpyrrolidinone as solvent make the reaction unsuitable for industrial use as these solvents can cause irritation to skin, eyes and respiratory tract. AU of the processes known in prior art for the preparation of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2- thienyl)propanamine, a key intermediate for the synthesis of duloxetine and pharmaceutically acceptable salts thereof involve the condensation of mono or disubstituted 3-hydroxy-3-(2- thienyl)propanamine with 1-halonaphthalene under different reaction conditions. The final product prepared by the most of the processes disclosed in the prior art shows the presence of a therapeutically inactive enantiomer, R-enantiomer which results in contamination of the final product, and reduces the yield by being a waste product and in extreme cases, might even be harmful to a patient being treated with a dosage form of the active pharmaceutical ingredient. The ICH Q7A guidance for active pharmaceutical ingredient manufacturers requires that such impurities be maintained below set limits.

The prior art provides processes for the purification of duloxetine hydrochloride wherein value of R- enantiomer in final product is reduced only from 2-3% to nearly 0%. Thus, there is a need in the art to develop a process for the preparation of the (S)-duloxetine substantially free of the R-enantiomer wherein the value of R-enantiomer in final product is reduced from more than 3% to acceptable levels to comply with the pharmacopoeial requirements in a facile manner. In view of the problems in the prior art processes, present invention provides an novel, efficient, operationally facile process for the preparation of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2- thienyl)propanamine, a key intermediate for the synthesis of duloxetine and pharmaceutically acceptable salts thereof. The process of the present invention is environmentally benign and amenable to scale up by avoiding the use of harmful reagents and stringent reaction conditions. Further, the present invention describes an industrially applicable, and reproducible process for the purification of duloxetine hydrochloride, which will enhance the purity of the final product, reducing the level of unwanted R-enantiomer from even 22% to 0.05% or nearly absent. OBJECT OF THE INVENTION The principal object of the invention is to provide an industrially advantageous process for the preparation of duloxetine and pharmaceutically acceptable salts thereof, specifically duloxetine hydrochloride.

Another object of the invention is to provide a novel and efficient process for the preparation of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine or acid addition salts thereof, involving 3-O-protected propanolamine derivative, useful synthetic intermediate. Another object of the invention is to provide a process for the preparation of duloxetine pharmaceutically acceptable salts, preferably duloxetine hydrochloride thereof via other duloxetine acid addition salts.

Yet another object of the invention is to provide a process for the purification of duloxetine pharmaceutically acceptable salts, preferably duloxetine hydrochloride for the removal of unwanted R-enantiomer from the final product. SUMMARY OF THE INVENTION

The present invention provides an efficient process for the preparation of duloxetine and pharmaceutically acceptable salt thereof, particularly duloxetine hydrochloride of formula I,

^HC1 Formula I in high yield and purity. According to one embodiment, the present invention provides a process for the preparation of duloxetine and pharmaceutically acceptable salts thereof from N,N-dimethyl-3-(l-naphthalenyloxy)- 3-(2-thienyl)-propanamine of formula II or acid addition salts thereof;

Formula II which is prepared by condensing 3-O-protected propanolamine derivative of formula III with 1- halonaphthalene in presence of suitable base in an organic solvent.

Formula III wherein R can be selected from straight chain or branched Cis alkyl, cycloalkyl, alkenyl, alkynyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, aminoalkyl or aminoaryl or heterocyclic ring with one or more hetero atom selected from nitrogen, oxygen or sulphur

3-<9-Protected propanolamine derivative of formula III is prepared by the reaction of the compound of formula IV,

Formula IV with a reactive derivative of an acid, whereas the compound of formula IV is prepared by a) reacting 2-acetylthiophene with ΛζiV-dimethylamine or acid addition salt thereof in the presence of paraformaldehyde in a suitable solvent to form compound of formula V or acid addition salts thereof; o 9 _nu Formula V

b) reducing the compound of formula V or acid addition salts thereof with a suitable reducing agent; and c) optionally, purifying the compound of formula V or acid addition salts thereof with an organic solvent.

According to another embodiment, the present invention provides a process for the preparation of duloxetine of formula I and pharmaceutical acceptable salts thereof by the process which comprises the step of a) condensing the 3-Oprotected propanolamine derivative of formula III, O R

^Λ-^J CH₃ Formula πi wherein R is as defined above with 1-halonaphthalene in presence of suitable base in an organic solvent to form compound of fonnula II or acid addition salts thereof; b) optionally, purifying the compound of formula II or acid addition salts thereof; and c) converting the compound of formula II or acid addition salts thereof to duloxetine and pharmaceutical acceptable salts thereof.

According to another embodiment, the present invention provides 3-0-protected propanolamine derivatives of formula III including salts, solvates, hydrates, polymorphs, racemates, isomers thereof, useful crucial intermediates in the preparation of duloxetine and pharmaceutically acceptable salts thereof.

According to one another embodiment, the present invention provides an industrially advantageous process for the preparation of highly pure duloxetine pharmaceutically acceptable salt, particularly duloxetine hydrochloride of formula I. The process comprises the step of: a) treating duloxetine with suitable acid to prepare duloxetine acid addition salt; b) converting duloxetine acid addition salt to duloxetine hydrochloride; and c) purifying duloxetine hydrochloride.

According to yet another embodiment, the present invention provides a process for the purification of duloxetine hydrochloride by using suitable solvent.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, all structural formulas include all possible. spatial configurations unless otherwise specifically indicated. In particular, compound that can exist as two enantiomers include the racemic mixture as well as other mixtures of (R) and (S) forms and the individual (R) and (S) enantiomer. For clarity, the designation of a specific enantiomer, in either words or fonnula, means that that the compound is relatively enantiomerically pure.

As used herein, unless the context requires otherwise, the "DNT" refers to racemic, mixture of (R) and (S)-isomer or individually(R) or (S)- isomers of N,N-dimethyl-3-(l-naphthenyloxy)-3-(2- thienyl) propanamine or acid addition salts thereof. As used herein "crystallization" refers to the foπnation of solid crystals from a homogeneous solution. It is essentially a solid-liquid separation technique. This process comprises: heating the product in a solvent to a temperature of between room temperature to reflux temperature of the solvent to obtain a solution, and cooling the solution to a room temperature.

As used herein "crude duloxetine hydrochloride " refers to duloxetine hydrochloride containing R- enantiomer as an impurity. The percentage of R-enantiomer is measured by chiral high performance liquid chromatography (HPLC). The percentage of R-enantiomer in the crude duloxetine hydrochloride ranges from 2.0 to 22.0%. Crude duloxetine hydrochloride can although synthetically be prepared by following prior art methods or by adding racemic duloxetine hydrochloride or by adding R-enantiomer of duloxetine hydrochloride obtained by concentrating the mother liquor of impure duloxetine hydrochloride. As used herein the "Enantiomeric purity" of duloxetine hydrochloride depends upon the level of its R-enantiomer, chemically known as (R)-(-)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride of following formula

The present invention provides a novel, efficient and industrially viable process for the preparation of duloxetine and pharmaceutically acceptable salts thereof, preferably duloxetine hydrochloride of formula I from DNT of formula II,

Formula II or acid addition salts thereof, which is prepared from 3-Oprotected propanolamine derivative of general formula III, which further forms a part of the present invention.

Formula III wherein R is as defined above

According to one embodiment, the present invention provides a novel process for the preparation of duloxetine and pharmaceutically acceptable salts thereof, preferably duloxetine hydrochloride starting from racemic or optically active isomer of 3-O-protected propanolamine derivative of general formula III. Specifically, 3-0-protected propanolamine derivative of general formula III is first converted to DNT or acid addition salts thereof which is then converted to duloxetine and pharmaceutically acceptable salts thereof.

DNT of formula II or acid addition salts thereof can be prepared by the condensation of 3-0- protected propanolamine derivative of formula III with 1-halonaphthalene under mild reaction conditions. The condensation reaction generally carried out in the presence of a suitable base in an organic solvent. Solvent employed includes, but not limited to halogenated hydrocarbons, ethers, aromatic hydrocarbons, esters, nitriles, polar aprotic solvents such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, JV-methyl pyrrolidine and the like. Preferably, the solvent is selected from acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl pyrrolidine and the like. The base employed can be organic or inorganic base. Inorganic base includes, but not limited to alkali metal hydroxides, carbonates, bicarbonates thereof such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. Organic base includes, organic amine such as alkyl amine, preferably triethylamine is used. The reaction can optionally be performed in the presence of phase transfer catalyst selected from crown ethers, quaternary ammonium salts, quaternary phosphonium salt or synthetic resins and the like. Preferably phase transfer catalyst can be selected from benzyltriethylammonium halide, tetrabutylammonium halide, 18-crown-6 and the like. The use of phase transfer catalyst facilitates the above reaction to be carried out under mild reaction conditions.. Usually the reaction is initiated at a temperature range of 20-50°C followed by heating the reaction mass at a temperature of about 60-100°C. The reaction mixture is further cooled to ambient temperature followed by the isolation of DΝT in high overall yield. Specific illustrations of suitable isolation procedures are described in the examples section that follows. However, other equivalent separation or isolation procedures could, of course, also be used. Filtration, centrifugation, decantation extraction and a combination of these procedures are the presently most preferred separation procedures.

Halonaphthalene employed can be selected from 1-fluoronaphthalene, 1-iodonaphthalene, 1- chloronaphthalene and 1-bromonaphthalene.

DΝT can be isolated from the reaction mixture or in situ converted to its acid addition salt. DΝT prepared by the above process can be purified by the suitable techniques known in the art such as crystallization, slurry wash, acid base treatment and the like or can be used as such for the preparation of duloxetine or pharmaceutically acceptable salt thereof. Preferably DΝT, if required can be purified by the acid base treatment. The process for the preparation of DΝT acid addition salt involves the treatment of DΝT or the reaction mixture containing the DΝT with a suitable acid. The acid employed for making DNT acid addition salts includes but not limited to organic acid such as

^• aliphatic or aromatic carboxylic acid (formic acid, acetic acid, oxalic acid, propanoic acid, maleic acid, citric acid, phthalic acid and the like); aliphatic or aromatic sulfonic acid such as toluene sulfonic acid, naphthalenesulphonic acid, methansulfonic acid, benzenesulfonic acid and the like; or inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid and the like. DNT acid addition salts, if required, can be purified by the suitable techniques known in the art such as crystallization, slurry wash and the like.

The DNT acid addition salt can be used as such for the preparation of duloxetine and pharmaceutically acceptable salts thereof or can be neutralized to give highly pure DNT base. Generally, the neutralization of acid addition salt carried out in presence of suitable base at a temperature of about 20 to 80 ⁰C, or from about 25 to 35 ⁰C. The reaction mixture will be maintained until its completion, such as for about 30 minutes to about 10 hours, or longer. Suitable base that can be used for conversion of DNT acid addition salt to DNT free base can be organic or inorganic base. Inorganic base includes but are not limited to alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, and the like. Organic base include alkyl amines like monoalkyl amine, dialkyl amine, trialkyl amine, preferably selected from methylamine, diethylamine, triethylamine and the like. The base can be used in the form of solid or in the form of aqueous solution. Suitably, aqueous solution of the corresponding base can be used. Any concentration is useful, which will convert the DNT acid addition salt to DNT free base. Suitable solvents which can be used for extracting the DNT free base from the reaction mixture includes, but are not limited to water immiscible solvent selected from halogenated hydrocarbons such as dichloromethane and the like; aliphatic or aromatic hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; esters such as ethyl acetate, propyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether and the like; and mixtures thereof. After completing the reaction, the organic layer containing the free base is separated and may be progressed to further processing directly or it can be first concentrated to form a residue. Preferably, optically active 3-O-protected propanolamine intermediate of general formula III is converted to optically active DNT or acid addition salt thereof. More preferably, (S)-DNT or acid addition salts thereof can be prepared from (S)-isomer of 3-O-protected propanolamine derivative of formula III or by the resolution of racemic DNT. In case of synthesis of many optically active substances, resolution or obtaining optically pure intermediates leads to better yields than resolving the final products.

The DNT base prepared by the process of present invention is pure. The DNT or its acid addition salt is then converted to duloxetine or acid addition salt thereof by following the demethylation methods well known in the art, such as described in US patent 5,023,269 and 5,362,886 or as described and exemplified in the context of the present invention.

Generally, demethylation of racemic or optically active DNT or acid addition salt thereof may be performed by treating racemic or optically active DNT with appropriate chloroformate such as phenyl chloroformate in an organic solvent to obtain the corresponding carbamate intermediate; hydrolyzing the carbamate intermediate with a base in an organic solvent to obtain racemic or optically active duloxetine. Preferably, a solution of (S)-N,N-dimethyl-3 -(I -naphthalenyloxy)-3 - (2-thienyl) propanamine in an inert solvent like toluene is treated with of phenyl chloroformate in the presence of diisopropylethylamine to prepare (S)-[N-Methyl-[3-(l-naphthalenyloxy)-3-(2- thienyl)propyl] carbamic acid]phenyl ester. The resulting carbamic acid phenyl ester is converted to duloxetine by treatment with suitable base particularly alkali metal hydroxide in an inert solvent like toluene. It is optional to isolate duloxetine from the reaction mixture; it can be in situ converted to duloxetine pharmaceutically acceptable or other acid addition salt.

According to another embodiment, the present invention provides a process for the enantiomerically pure duloxetine pharmaceutically acceptable salts specifically, duloxetine hydrochloride of formula I from duloxetine free base via its other acid addition salts.

Generally, duloxetine free base is treated with a suitable acid to from duloxetine acid addition salt which is then converted to duloxetine hydrochloride in presence of a source of hydrochloride. In one preferred embodiment, duloxetine hydrochloride can be prepared from duloxetine free base via its other acid addition salt using hydrochloric acid in the absence of organic solvent. Specifically, duloxetine free base is dissolved in a suitable solvent selected from C_1-4 alcohol, ester preferably ethyl acetate followed by the addition of suitable acid. The reaction mixture is stirred for few minutes to few hours at a suitable temperature till the completion of the reaction. Preferably, the reaction mixture is stirred for 1-3 hours at about ambient temperature, filtered and dried to obtain duloxetine acid addition salt. Preferred acid addition salts commonly employed include those formed with organic acid selected from C_1-I0 aliphatic carboxylic acid, aryl carboxylic acid, hetero-aryl carboxylic acid, aryl alkyl carboxylic acid, oxalic acid, citric acid, maleic acid, formic acid, fumaric acid, acetic acid; inorganic acid like hydrobromic acid, hydroiodic acid. Particularly oxalic acid and fumaric acid are employed. The duloxetine acid addition salts can be isolated by conventional methods like spray drying, evaporation, vacuum drying and the like.

Duloxetine acid addition salt in water is treated with hydrochloric acid to prepare duloxetine hydrochloride. After completion of reaction duloxetine hydrochloride is extracted in non-polar organic solvent immiscible with water. Non-polar organic solvents can be selected from chlorinated hydrocarbons like dichloromethane, dichloroethane, chloroform, carbon tetrachloride; aromatic hydrocarbons like benzene, ethylbenzene, toluene, xylene; cyclic and acyclic hydrocarbons like pentane, hexane, heptane, cyclohexane; ethers like diethyl ether, isopropyl ether, methyl tertiary butyl ether; esters like ethyl acetate, butyl acetate, methyl acetate; the preferred being dichloromethane.

In another preferred embodiment, duloxetine hydrochloride can be prepared from duloxetine free base via its other acid addition salt using hydrochloride salt of base in protic solvent. Specifically, duloxetine free base is dissolved in a suitable solvent selected from C_1-4 alcohol, ester preferably ethyl acetate, followed by the addition of suitable acid. Suitable acid employed are same as defined above. The reaction mixture is stirred for few hours to few minutes at a suitable temperature till the completion of the reaction. Preferably, the reaction mixture is stirred for 1-3 hours at about ambient temperature, filtered and dried to obtain duloxetine acid addition salt. Duloxetine acid addition salt is further refluxed with hydrochloride salt of suitable base in a protic solvent. Suitable base can be selected from organic amines such as ammonia, N,N-dimethylamine, pyridine and the like. Protic solvent can be selected from water, C_1-6 alcohol like methanol, ethanol, specifically methanol. The reaction mixture is then cooled to ambient temperature and protic solvent is distilled off under vacuum. The product is then extracted with non polar organic solvent immiscible with water. The non polar organic solvent is same as discussed above. The product can be isolated by conventional methods like spray drying, evaporation, vacuum drying, and the like. According to another embodiment, the present invention provides a process for the purification of crude duloxetine hydrochloride for the removal of unwanted R-enantiomer to afford highly pure duloxetine hydrochloride.

Specifically, crude duloxetine hydrochloride, is crystallized in C_1-5 alkylnitrile, or a mixture of alkylnitrile with solvent selected from a C_2-8 ether, a Cs_-8 aliphatic or C_6-12 aromatic hydrocarbon, C_1- 8 ester C_3-10 ketone, and halogenated hydrocarbons, straight chain or branched C_1-8 aliphatic alcohol, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, N-methylpyrrolidine, and sulfolane. Preferably the solvent is acetonitrile, propionitrile, toluene, methylisobutyl ketone, diisopropyl ether, ethyl acetate. Typically, crude duloxetine hydrochloride in the suitable solvent is heated to the reflux temperature of the solvent till a clear solution is obtained for a time sufficient to obtain highly pure duloxetine hydrochloride having purity greater than 99% by HPLC, wherein the ratio of R- enantiomer is found to be less than 0.15%, more preferably less than 0.05%.

The crystallization process may be repeated in order to increase the purification even further either with the same or a different solvent or solvent mixture that is used for the first crystallization.

The duloxetine and pharmaceutically acceptable salt thereof can be purified any suitable techniques known in the art such as slurry wash or as described in the present invention. The duloxetine pharmaceutically acceptable salts can be purified by dissolving the duloxetine salt, preferably duloxetine hydrochloride in a suitable solvent followed by carbon treatment to obtain highly pure duloxetine pharmaceutically acceptable salts. Suitable solvent include C_1-5 alcohol such as methanol and the like. The final compound can be purified by one of the above technique or in combination with other can be employed.

Starting compound, 3-<9-Protected propanolamine derivative of formula III can be prepared by the processes well known in the art. Specifically, the 3-O-protected propanolamine derivative of foπnula III can be prepared by the reaction of compound of formula IV,

OH

«;^S)^^N^CH3

^ CH₃ Formula IV with a reactive derivative of organic acid in the presence of a base optionally along with catalytic amount of iV,iV-dimethyl amino pyridine. Reactive derivative of acid can preferably be selected from alkyl or aryl carboxylic acid chloride such as acetyl chloride, propionic acid chloride, butyric acid chloride, benzoyl chloride and the like; alkyl or aryl carboxylic acid anhydride or mixed anhydride such as acetic anhydride, butyric anhydride, propionic anhydride and the like. Base can be selected from tertiary amines, metal carbonates and bicarbonates. Preferably base include triethylamine, trimethylamine, N-methylmorpholine, ΛζN'-dimethylpiperidine; iV,iV-dimethylanilme, pyridine, 1,8- bis(dimethylamino) naphthalene, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, cesium carbonate etc.

Optically active (S)-isomer of the 3-O-protected propanolamine derivatives of formula III can be prepared from their racemic precursor by using resolving agent and repeated crystallization, by chromatography or by the methods well known in the art. Specific illustrations of suitable resolution procedures can be had by reference to the examples herein below. Particularly resolving agents include chiral acids like tartaric acid, camphor sulfonic acid, camphoric acid, JV-protected amino acids, mandelic acid, malic acid, tartaric acid, diaryl tartaric acid, di-p-tolyl tartaric acid, O,O'- dibenzoyltartaric acid, glucuronic acid, naproxen or ascorbic acid and the like in a solvent suitable for the purpose. Preferably di-p-tolyl tartaric acid is used as a resolving agent. Alternatively, optically active 3-<9-protected propanolamine derivatives of formula III is prepared by the reaction of optically active compound of formula IV with a reactive derivative of organic acid in the presence of a base optionally along with catalytic amount of N,iV-dimetliyl amino pyridine. Preferably, (S)-isomer of 3-0-protected propanolamine derivatives of formula III is prepared from (S)-isomer compound of formula IV.

The 3-<9-protected propanolamine derivative of formula III is then converted to DΝT or acid addition salts thereof by process described in the present invention. Preferably, the (S)-DΝT is particularly preferred, since it a key intermediate of (S)-duloxetine, a pharmaceutically active compound.

The compound of formula IV can be prepared by the methods reported in prior art such as US patent 5,362,886, and in an Article ' Organic Process Research and Development, 2006, 10, 905-913'. Generally, compound of formula IV can be prepared starting from 2-acetylthiophene. The reaction involves the condensation of 2-acetylthiophene with iV.N-dimethylamine or acid addition salt thereof (preferably hydrochloride salt) in presence of paraformaldehyde in a suitable solvent selected from C_1-6 alcohol preferably ethanol, isopropyl alcohol and the like under Mannich reaction conditions to give N,N-dimethyl-3-oxo-3-(2-thienyl)-propanamine of formula V or acid addition salt thereof, preferably hydrochloride salt,

Formula V

The compound 2-acetylthiophene may contain impurity of 3-acetylthiophene which, if present, may get carried over to intermediate N,N-dimethyl-3-oxo-3-(2-thienyl)-propanamine or acid addition salt thereof. Thus it become necessary to remove impurities at initial stages of process because they can further get carried over to final product and reduces the yield as well as purity of final product. The intermediate so formed, if desired, can be purified in a suitable solvent that include, but not limited to nitriles, mixture of nitriles with other solvents which includes but not limited to alcohols, ketones and water. Preferably acetonitrile or aqueous acetonitrile is employed as solvent for purification. The intermediate compound of formula V or acid addition salts thereof is then reduced in the presence of suitable reducing agent to give compound of formula IV.

Formula IV Reducing agent can be selected from alkali metal borohydride such as sodium borohydride, potassium borohydride, and lithium borohydride in a suitable solvent. Suitable solvent includes C_1-5 alcohols. The intermediate compound of formula V can be reduced enantioselectively to give optically active isomers of compound of formula IV. The racemic isomers prepared can be resolved with a suitable chiral acid by employing the processes known in the art.

Optically active compound of formula IV can be prepared by resolving the racemic precursor and is achieved by the reaction of racemic compound of formula IV with a suitable chiral acid in a suitable solvent like methyl tertiarybutyl ether, toluene and the like and a co solvent like ethanol, methanol and the like at a temperature of about 0-60 °C for time sufficient to convert to the corresponding chiral acid salt. The chiral acid include, but not limited to mandelic acid, tartaric acid, camphor sulfonic acid, malic acid, camphoric acid, diaryl tartaric acid, di-p-tolyl tartaric acid, O,O'- dibenzoyltartaric acid, glucuronic acid, naproxen or ascorbic acid and the like. Preferably, mandelic acid is used as a resolving agent. The chiral acid salt of formula IV, if required, is further purified to get rid of the unwanted impurities like R-enantiomer by treating with a suitable solvent at a temperature of about 20 - 95 ⁰C, preferably till complete dissolution to form highly pure chiral acid salt of formula IV. Solvent include, but not limited to alcohol such as methanol, ethanol, isopropanol and the like; aliphatic or aromatic hydrocarbon such as toluene, xylene and the like. The chiral acid salt so formed is then converted to optically active isomer of formula IV by reaction with a suitable base in a suitable solvent at a temperature of about 0-25 ⁰C. Base includes but not limited to alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or alkali metal carbonate/bicarbonate such as potassium carbonate etc. Suitable solvent include aliphatic or aromatic hydrocarbon such as toluene and the like; ether such as diisopropylether, methyl tert- butylether and the like or mixture thereof. Major advantages realized in the present invention is that process described here for the preparation of duloxetine and pharmaceutically acceptable salts thereof is cost effective, eco-friendly, commercially viable as well as reproducible on industrial scale and meets the needs of regulatory agencies. Moreover, duloxetine hydrochloride obtained by processes of the present invention is highly pure, wherein the level of unwanted R-enantiomer is reduced from more than 2% or as high as 22% to nearly absent. Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow. EXAMPLES:

Example 01: Preparation of 7V,N-dimethyl-3-oxo-3-(2-thienyI)-propanamine hydrochloride A mixture of 2-acetylthiophene (800 g), N,N-dimethylamine hydrochloride (652.2 g), paraformaldehyde (282.1 g), concentrated hydrochloric acid (30.3 ml) and isopropyl alcohol (2.4 It) was refluxed for 5 hours followed by cooling to 20-25 ⁰C. The solid thus obtained, was filtered, washed with isopropyl alcohol (800 ml) and dried to obtain 1.194 kg of title compound having purity 99.29% by HPLC. Example 02: Purification of iV,iV-dimethyl-3-oxo-3-(2-thienyl)-propanamine hydrochloride

A solution of N,N-dimethyl-3-oxo-3-(2-thienyl)-propanamine hydrochloride (1 g, having impurity 3- isomer 0.33% by HPLC) in acetonitrile (5 ml) was refluxed for 30 minutes and then stirred at 25-30 ⁰C for 2 hours. The reaction mixture was filtered and dried to obtain 0.9 g of title compound having impurity 3 -isomer 0.18% by HPLC. Example 03: Preparation of (+)-ΛyV-dimethyl~3-hydroxy-3-(2-thienyl)-propanamine

To a solution of sodium hydroxide (237 g), sodium borohydride (102.17 g) and demineralized water (3.55 It), was added N,N-dimethyl-3-oxo-3-(2-thienyl)-propanamine hydrochloride (1.185 kg) at 10- 15 ⁰C. The solution was stirred for 3 hours at 20-25 ⁰C, and then heated to 70 ⁰C for one hour. The reaction mixture was cooled to 0 ⁰C, and treated with concentrated hydrochloric acid (1.017 It) at 0- 10 ⁰C, and washed with n-heptane (1x2.3 It; 2x1.2 It) at 30-35 ⁰C. The aqueous layer was cooled to 10-15 ⁰C, basified with aqueous sodium hydroxide solution (277 g in 277 ml demineralized water) at 10-15 ⁰C and extracted with toluene at 30-35 ⁰C (2x3.56 lt+ 1x2.3 It). Combined toluene layer was washed with water (1.18 It). Some of the solvent was distilled off followed by addition of anhydrous toluene (1.0 lt).The toluene solution thus obtained was used as such for the next stage. Example 04: Preparation of (S)-iV,iV-dimethyl-3-hydroxy-3-(2-thienyl)-propanamine

To toluene solution of (+)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)-propanamine was added methanol (500 ml) and S-(+)-mandelic acid (410.7 g) at 50-55 ⁰C and reaction mixture was refluxed. The reaction mixture was then cooled to 60-62 ⁰C and seeded with pure (S)-mandelate salt of title compound (1.0 g) at 60-62 ⁰C, and allowed to cool to 22-23 ⁰C. The precipitated product was filtered, washed with toluene (1.2 It) and dried to obtain mandelate salt of the title compound having chiral purity 96%, R-isomer 4% by HPLC.The mandelate salt (680 g) so obtained was suspended in a mixture of toluene (6.8 It) and methanol (170 ml) and heated until a clear solution was obtained. The reaction mixture was then cooled to 60-62 ⁰C and seeded with pure (S)-mandelate salt of title compound (1.0 g) at 60-62 ⁰C, and allowed to cool to 20-25 ⁰C. The precipitated product was filtered, washed with toluene (680 ml) and dried to obtain pure mandelate salt of the title compound having chiral purity 98.4 %, R-isomer 1.6% by HPLCTo a mixture of mandelate salt (625 g) in toluene (2.5 It) was added a solution of sodium hydroxide (111.5 g) in demineralized water (557 ml) at 30-35 ⁰C and reaction mixture was stirred for 30 minutes. The layers were separated and aqueous layer was extracted with toluene (1.2 It). Combined organic layer was washed with water. Solvent was distilled off under vacuum to obtain pure title compound which was used as such for next stage. Example 05: Preparation of (S)-iV,Λ'-dimethyl-3-hydroxy-3-(2-thienyl)-propanamine A solution of (S)-(+)mandelic acid (41.6 g) in ethanol (240 ml) was added to a stirred solution of (±)-N,iV-dimethyl-3-hydroxy-3-(2-thienyl)-propanamine (101 g) in methyl tertiary butyl ether (1180 ml) at 50-55 ⁰C, stirred for 45 minutes and then at 25-30 ⁰C for one hour. The precipitated product was filtered, washed with methyl tertiary butyl ether (200 ml) and dried to obtain 78 g of the mandelate salt of the title compound. The mandelate salt so obtained was suspended in a mixture of toluene (780 ml) and methanol (19.5 ml) was heated at 80-85 ⁰C till complete dissolution. The reaction mixture was stirred for 30 minutes and then stirred at 25-30 ⁰C for one hour. The reaction mixture was filtered, washed with toluene (80 ml) and dried to obtain 74 g of the mandelate salt of the title compound. Aqueous sodium hydroxide (13.2 g in 148 ml water) was added to a suspension of the above mandelate salt (74 g), in toluene (370 ml) at 20 -25 ⁰C and stirred for 30 minutes. The layers were separated and organic layer was washed with brine followed by water. Solvent was distilled off under vacuum to obtain 39 g of the title compound.

Example 06: Preparation of (S)-7V,Λ^r-dimethyl-3-acetoxy-3-(2-thienyl)-propanamine (S)-N,N-Dimethyl-3-hydroxy-3-(2-thienyl)-propanamine (100 g) was added to a mixture of acetic anhydride (60.64 g) and triethylamine (65.5 g) in dichloromethane (500 ml) at 25-35 ⁰C and stirred for 2 hours. Water (200 ml) was added to the reaction mixture and reaction mixture was extracted with dichloromethane. All organic extracts were combined, washed with water and distilled off to obtain 12O g of title compound.

Example 07: Preparation of (S)-iV,iV~dimethyl-3-acetoxy-3-(2-thienyl)-propanamine To a toluene solution of (S)-AζN-dimethyl-3-hydroxy-3-(2-thienyl)-propanamine (obtained in example 4) was added triethylamine (224 g) and acetic anhydride (208 g) at 30-35 ⁰C. The reaction mixture was stirred for 2 hours at 30-35 ⁰C followed by addition of demineralized water (680 ml). The layers were separated. The toluene layer was washed with demineralized water (680 ml). Toluene was distilled off to obtain 415 g of title compound having purity 99.96% by HPLC. Example 08: Preparation of (+)-iV,Λ'-dimethyl-3-acetoxy-3-(2-thienyl)-propanamine

N,N-Dimethyl-3-hydroxy-3-(2-mienyl)-propanamine (10 g) was added to a mixture of acetic anhydride (6.06 g), triethylamine (6.5 g) in toluene (50 ml) at 30-35 ⁰C, stirred for 2 hours. Water (20 ml) was added to the reaction mixture and extracted with toluene. All organic extracts were combined, washed with water and distilled off to obtain 12.2 g of title compound.

Example 09: Preparation of (S)-iV,iV-dimethyl-3-acetoxy-3-(2-thienyl)-propanamine A solution of L-(+)di-p-tolyl-tartaric acid (0.42 g) in ethyl acetate (2 ml) was added to a solution of (±)-N,N-dimethyl-3-acetoxy-3-(2-thienyl)-propanamine (1 g) in ethyl acetate (3 ml) at 20-25 ⁰C, and stirred for 2 hours. The precipitates was filtered, washed with ethyl acetate (1 ml) and dried to obtain 0.7 g of the corresponding di-p-tolyl-tartarate salt of title compound.

To a mixture of the salt obtained (0.4 g) and triethylamine (0.1 g) in toluene (3 ml) at 20-25 ⁰C, was added water (2 ml) and stirred for 10 minutes. Layers were separated and toluene layer was washed with water. The toluene was distilled off to obtain 0.12 g of the title compound. Example 10: Preparation of (S)-N,7V-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)- propanamine

To a solution of (S)-N,N-dimethyl-3-acetoxy-3-(2-thienyl)-propanamine (380 g) and dimethylsulfoxide (1.9 It) was added sodium hydroxide (268 g) at 10-15 ⁰C. The reaction mixture was stirred for one hour at 20-25 ⁰C followed by addition of 1-fluoronaphthalene (294 g). Reaction mixture was heated to 70-75 ⁰C and stirred at 70-75 ⁰C till completion of reaction (as monitored by thin layer chromatography). Reaction mixture was cooled to 0-10 ⁰C followed by addition of aqueous hydrochloric acid (2.04 It hydrochloric acid in 3.8 It water). The aqueous layer was extracted with toluene (2x1.9 It, lxl.O It). All the organic extracts were combined and washed with water (760 ml). Toluene was distilled off to obtain 556.7 g of title compound having purity 94.76% by HPLC. Example 11: Preparation of (S)-iV,N-dimethyI-3-(l-naphthalenyloxy)-3-(2-thienyl)- propanamine

To a solution of (S)-N,N-dimethyl-3-acetoxy-3-(2-thienyl)propanamine (50 g) and dimethylsulfoxide (250 ml) was added sodium hydroxide (35.2 g) and further stirred for one hour at 25-30 ⁰C. 1-Fluoronaphthalene (38.6 g) was added to the reaction mixture, stirred for 20 hours at 70- 75 ⁰C, cooled to 20-25 ⁰C followed by the addition of water (500 ml). Reaction mixture was extracted with toluene, washed with brine followed by water. Solvent was distilled to obtain 75 g of the title compound. Example 12: Preparation of (S)-N,iV-dimethyl-3-(l-naphthaIenyloxy)-3-(2-thienyl)- propanamine

To a solution of (S)-N,7V-dimethyl-3-acetoxy-3-(2-thienyl)propanamine (10 g) and dimethylsulfoxide (50 ml) was added sodium hydroxide (7.04 g) and further stirred for one hour at 25-30 ⁰C. 1-Fluoronaphthalene (7.7 g) was added to the reaction mixture, stirred for 20 hours at 70- 75 ⁰C and cooled to 20-25 ⁰C followed by the addition of water (100 ml). Reaction mixture was extracted with toluene, washed with brine followed by water. Solvent was distilled off to obtain 15 g of the title compound having purity 95.89% by HPLC. Example 13: Preparation of (S)-N,iV-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)- propanamine

To a solution of (S)-N,N-dimethyl-3-acetoxy-3-(2-thiemyl)-propanamine (21.5 g) in dimethylsulfoxide (105 ml), sodium hydroxide (15.15 g) and benzyltriethylammonium chloride (2.15 g) were added and stirred for one hour at 25-30 ⁰C. 1-Fluoronaphthalene (16.69 g) was added to the reaction mixture and stirred for 20 hours at 70-75 ⁰C. Thereafter, the reaction mixture was cooled to 20-25 ⁰C and diluted with water (200 ml). The reaction mixture was extracted with toluene. Combined toluene extracts were washed with brine, followed by water. Solvent was distilled off under vacuum to obtain 29 g of title compound.

Example 14: Purification of (S)-iV,iV-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)- propanamine To a solution of (S)-N,iV-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine (521 g, having purity 94.76% by HPLC) in ethyl acetate (1.6 It) was added a solution of oxalic acid (210 g) in ethyl acetate (2.1 It) at 60-65 ⁰C. Reaction mixture was stirred for one hour at 60-65 ⁰C. The ethyl acetate was distilled off under vacuum followed by addition of n-heptane (2.0 It). Thereafter, the reaction mixture was cooled to 20-25 ⁰C. The solid precipitated out was filtered, washed with n-heptane (520 ml) and dried under vacuum. To a mixture of this compound in toluene (2.1 It), a solution of potassium carbonate (346.8 g in 1.71 It water) was added. The reaction mixture was stirred for one hour and layers were separated. The organic layer was washed with demineralized water (1.0 It). Solvent was distilled off to obtain 466.27 g of title compound having purity 96.81 % by HPLC Example 15: Purification of (S)-iV,iV-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)- propanamine

To a solution of (S)-N,iV-dimethyl-3-(l-naphthalenyloxy)-3-(2-mienyl)-propanamine (15 g, having purity 95.89 % by HPLC) in ethyl acetate (46 ml) was added a solution of oxalic acid (6.05 g) in ethyl acetate (60.5 ml) at 60-65 ⁰C. Reaction mixture was stirred for one hour at 60-65 ⁰C. The ethyl acetate was distilled off under vacuum followed by addition of n-heptane (57.58 ml). The reaction mixture was cooled to 20-25 ⁰C. The solid precipitated out was filtered, washed with n-heptane (15 ml) and dried under vacuum. To a mixture of oxalate salt of title compound prepared above in toluene (60.5 ml) was added solution of potassium carbonate (10 g in 50 ml water). The reaction mixture was stirred for one hour and layers were separated. The organic layer was washed with demineralized water (29 ml). Toluene was distilled off to obtain 13.0 g of title compound having purity 98.28 % by HPLC

Example 16: Purification of (S)-iV,iV-dimethyl-3-(l-naphthalenyIoxy)-3-(2-thienyl)- propanamine To a solution of (S)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine (20 g, having purity 94.20 % by HPLC) in methanol (160 ml) was added aqueous solution of oxalic acid (8.1 g in 40 ml demineralized water) and stirred for 30 minutes at 25-30⁰C. The reaction mixture was washed with n-heptane (2x80 ml). Potassium carbonate (13.3 g) was added to the reaction mixture and stirred for 30 minutes at 25-30 ⁰C. Methanol was distilled under vacuum. Toluene (80 ml) and demineralized water (40 ml) were added to above residue and stirred for 30 minutes at 25-30 ⁰C. Toluene layer was separated and aqueous layer was extracted with toluene (40 ml). Combined toluene layer was washed with demineralized water (40 ml) and distilled under vacuum to obtain 17.2 g of title compound having purity 95.59% by HPLC. Example 17: Preparation of (S)-iV,7V-dimethyl-3-benzoyloxy-3-(2-thienyl)-propanamine (S)-N,N-Dimethyl-3-hydroxy-3-(2-thienyl)-propanamine (50 g) was added to a mixture of benzoylchloride (41.79 g) and triethylamine (32.75 g) in dichloromethane (250 ml) at 25-35 ⁰C and stirred for 2 hours. Water (100 ml) was added to the reaction mixture and extracted with dichloromethane. All organic extracts were combined, washed with water and distilled off to obtain 75 g of title compound. Example 18: Preparation of (S)-iV,N-dimethyl-3-(l-naphthalenyloxy)~3-(2-thienyl)- propanamine

To a solution of (S)-N,N-dimethyl-3-benzoyloxy-3-(2-thienyl)-propanamine (2 g) and dimethylsulfoxide (10 ml) was added sodium hydroxide (1.1 g) and further stirred for one hour at 25-30 ⁰C. 1-Fluoronaphthalene (1.21 g) was added to the reaction mixture, stirred for 20 hours at 70- 75 ⁰C, cooled to 20-25 ⁰C followed by the addition of water (20ml). Reaction mixture was extracted with toluene, washed with brine followed by water. Solvent was distilled off to obtain 2.1g of the title compound. Example 19: Preparation of (S)-duloxetine

A solution of (S)-i\ζiV-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine (425 g) in toluene (2.13 It) was azeotroped at 120 ⁰C for one hour and cooled to 25 ⁰C. Diisopropyl ethylamine (194 g) was added followed by addition of phenylchloroformate (320 g). The reaction mixture was stirred for 2 hours at 30-35 ⁰C and was quenched with IN hydrochloric acid (850 ml) at 25 ⁰C. The layers were separated. The organic layer was washed with aqueous sodium bicarbonate (850 ml, 15%) followed by water (850 ml). Toluene (1 It) was distilled off under vacuum and used as such for next stage. A solution of potassium hydroxide (379g) in toluene (1.63 It) was azeotroped for one hour and cooled to 40-45 ⁰C, followed by addition of above prepared toluene solution at 40-45 ⁰C. Reaction mixture was heated to 90-95 ⁰C for 4 hours, cooled to 20-25 ⁰C, followed by addition of aqueous hydrochloric acid (165 ml concentrated HCl in 1.13 It water) at 20-25 ⁰C. The layers were separated and aqueous layer was extracted with toluene (2x1.13 It). AU the organic extracts were combined and washed with demineralized water (1.13 It). The toluene was distilled off to obtain 534.5 g of title compound having purity 90.0% by HPLC.

Example 20: Preparation of (S)-duIoxetine hydrochloride

Ethyl acetate hydrochloride (480 ml, 10% HCl solution) was added to a solution of (S)-duloxetine (534.5 g) in ethyl acetate (3.16 It) at 0-5 ⁰C. After stirring for one hour, the reaction mixture was filtered, washed with ethyl acetate (790 ml) and dried to obtain 310 g of title compound having purity 98.5% by HPLC.

Example 21 : Purification of (S)-duloxetine hydrochloride

A solution of (S)-duloxetine hydrochloride (300 g) in acetonitrile (2.1 It) was heated at 80-85 ⁰C until a clear solution was obtained. Solution was cooled to 20-25 ⁰C and stirred for one hour at 20- 25 ⁰C. The solution was filtered, washed with acetonitrile (300 ml) and dried to obtain 269 g of title compound having purity 99.82 % by HPLC.

Example 22: Purification of (S)-duloxetine hydrochloride

To a solution of (S)-duloxetine hydrochloride (250 g) in methanol (1 It) at 20-25 ⁰C was added activated carbon (25 g) and stirred for 30 minutes at 20-25 °C. Carbon was filtered through hyflo bed followed by removal of solvent under vacuum. Acetonitrile (1.75 It) was added and heated to 80-85 ⁰C. Solution was cooled to 0-5 ⁰C and stirred for one hour at 0-5⁰C. The solution was filtered, washed with chilled acetonitrile (500 ml) and dried to obtain 23O g of title compound having purity 99.89% by HPLC. Example 23: Preparation of duloxetine free base

A solution of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine (50.0 g) in toluene (300 ml) was heated to reflux and azeotroped under stirring for one hour. The temperature was lowered to 35-40 ⁰C, diisopropylethylamine (22.8 g) followed by phenylchloroformate (37.7 g) were added and stirred at 30-35 °C for one hour. The reaction mass was washed with IN hydrochloric acid (100 ml), demineralised water (100 ml), 5% ammonium hydroxide (100 ml) and finally with demineralised water (100 ml). Toluene was distilled off under reduced pressure to obtain compound (S)-(+)-[N-methyl-[3-(l-naphthalenyloxy)-3-(2-thienyl)propyi] carbamic acid]phenyl ester. This compound was added to a pre-azeotroped suspension of potassium hydroxide (27 g) in toluene (336 ml) and again refluxed and azeotroped for 2 hours. The reaction mass was cooled to 25-30 ⁰C and washed with water. The organic layer was distilled off in vacuum to obtain 46 g of duloxetine free base having purity of 90.0% by HPLC containing 7% R-enantiomer. Example 24: Preparation of duloxetine hydrochloride

(I) Preparation of duloxetine oxalate Duloxetine free base (23.0 g, containing 7% R-enantiomer) was dissolved in ethyl acetate (46 ml) and then solution of oxalic acid (9.8 g) in ethyl acetate (69 ml) was added. Reaction mixture was stirred for one hour at 25-30 ⁰C. Filtered and dried the solid to obtain 27 g of oxalate of title compound having purity of 94.51% by HPLC.

(II) Preparation of duloxetine hydrochloride A solution of duloxetine oxalate salt prepared above, in water (27 ml) and 2Ν hydrochloric acid (54 ml) was stirred for 30 minutes. After completion of reaction, dichloromethane (135 ml) was added. The layers were separated and the organic layer was washed with brine (saturated aqueous sodium chloride solution).Organic layer was concentrated in vacuum to obtain 21.0 g of title compound having purity of 94.77% by HPLC containing 6.4% R-enantiomer. Example 25: Purification of duloxetine hydrochloride

Method A: A mixture of duloxetine hydrochloride (1.0 g, HPLC purity: 94.77%, containing 6.4% R-enantiomer), toluene (4.5 ml) and acetonitrile (0.5 ml) was heated to 90-95 ⁰C, followed by stirring at 25-30 ⁰C for 2 hours. The solid was filtered and dried in a vacuum oven to obtain 0.8 g of title compound having purity of 97.78% by HPLC containing 3.2% R-enantiomer. The resulting compound in acetonitrile (5.5ml) was heated to reflux to clear solution, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 0.52 g of title compound having purity of 99.55% by HPLC containing 0.01% R-enantiomer. Method B; A mixture of duloxetine hydrochloride (1.0 g, HPLC purity: 94.77% containing 6.4% R- enantiomer), toluene (4 ml) and acetonitrile (1 ml) was heated to 90-95 ⁰C, followed by stirring at 25-30 ⁰C for 2 hours. The solid was filtered and dried in a vacuum oven to obtain 0.65 g of title compound having purity of 99.58% by HPLC containing 0.85% R-enantiomer. The resulting compound in acetonitrile (4.5ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 0.50 g of title compound having purity of 99.65% by HPLC containing 0.02% R-enantiomer. Method C; A mixture of duloxetine hydrochloride (1.0 g, HPLC purity: 94.77% containing 6.4% R- enantiomer), toluene (2.5 ml) and acetonitrile (2.5 ml) was heated to 80-95 ⁰C till complete dissolution, followed by stirring at 25-30 ⁰C for 2 hours. The solid was filtered and dried in a vacuum oven to obtain 0.4 g of title compound having purity of 99.51% by HPLC containing 0.6% R-enantiomer.

The resulting compound in acetonitrile (2.7 ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 0.26 g of title compound having purity of 99.58% by HPLC containing 0.05% R-enantiomer. Method D: A mixture of duloxetine hydrochloride (1.0 g, HPLC purity: 94.77% containing 6.4% R- enantiomer), diisopropyl ether (2.5 ml) and acetonitrile (2.5 ml) was heated to reflux, followed by stirring at 25-30 ⁰C for 2 hours. The solid was filtered and dried in a vacuum oven, to obtain 0.75 g of title compound having purity of 97.86% by HPLC containing 3.4% R-enantiomer. The resulting compound in acetonitrile (5.5 ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 0.48 g of title compound having purity of 99.55% by HPLC containing 0.02% R-enantiomer. Method E: A mixture of duloxetine hydrochloride (1.0 g, HPLC purity: 94.77% containing 6.4% R- enantiomer), methyl iso-butyl ketone(4.95 ml) and acetonitrile (0.05 ml) was heated to 90-95 ⁰C, followed by stirring at 25-30 ⁰C for 2 hours. The solid was filtered and dried in a vacuum oven, to obtain 0.82 g of title compound having purity of 98.51% by HPLC containing 3.35% R-enantiomer. The resulting compound in acetonitrile (5.8 ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30 ⁰C for one hour. The solid was filtered and dried in a vacuum oven to obtain 0.55 g of title compound having purity of 99.55% by HPLC containing 0.02% R-enantiomer. Method F: A mixture of duloxetine hydrochloride (2.5 g, HPLC purity: 94.77% containing 6.4% R- enantiomer), methyl iso-butyl ketone (9.5 ml) and acetonitrile (0.5 ml) was heated to 90-95 ⁰C, followed by stirring at 25-30 ⁰C for 2 hours. The solid was filtered and dried in a vacuum oven to obtain 2.0 g of title compound having purity of 99.60% of HPLC containing 4% R-enantiomer. The resulting compound (1.0 g, HPLC purity 99.60% containing 4% R-enantiomer), propionitrile (6 ml) was heated to reflux, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 0.65 g of title compound containing 0.56% R-enantiomer. Method G: A mixture of duloxetine hydrochloride (1.0 g, HPLC purity: 94.77% containing 6.4% R-enantiomer), ethyl acetate (4.75 ml) and acetonitrile (0.25 ml) was heated to reflux, followed by stirring at 25-30 ⁰C for 2 hours. The solid was filtered and dried in a vacuum oven to obtain 0.6 g of title compound having purity of 98.54% by HPLC containing 2.8% R-enantiomer. The resulting compound in acetonitrile (4.5 ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 0.39 g of title compound having purity of 99.59% by HPLC containing 0.04 % R-enantiomer. Method H: A mixture of duloxetine hydrochloride (3 g, HPLC purity: 94.77% containing 6.4% R- enantiomer) in acetonitrile (21 ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 1.8 g of title compound having purity of 99.6% by HPLC containing 0.1% R enantiomer. Example 26: Preparation of duloxetine hydrochloride (I) Preparation of duloxetine oxalate

A solution of duloxetine free base (10 g, HPLC purity: 90.0% containing 7% R-enantiomer) in ethyl acetate (40 ml) was added to a solution of oxalic acid (4.4 g) in ethyl acetate (60 ml), stirred for one hour at 25-30⁰C. Filtered and dried the solid to obtain 12.0 g of duloxetine oxalate. (II) Preparation of duloxetine hydrochloride

Duloxetine oxalate (10 g) and ammonium chloride (2.8 g) in methanol (40 ml) was refluxed for 5 hours, cooled to room temperature. Methanol was distilled off in vacuum. Water (40 ml) and dichloromethane (80 ml) was added to above solution and stirred for 30 minutes. The organic layer was separated, washed with water, and concentrated in vacuum to obtain 1O g of the title compound having purity of 93.89% by HPLC.

Example 27: Purification of duloxetine hydrochloride

Method A: A mixture of duloxetine hydrochloride (2.5 g, HPLC purity: 93.89% containing 7% R- enantiomer), in ethyl acetate (12.5ml) was heated to 8O⁰C for 30 minutes and then for one hour at 25-30 ⁰C. The solid was filtered and dried to obtain 1.1 g of title compound having purity of 98.70% by HPLC containing 4% R-enantiomer.

The resulting compound (1.1 g) in acetonitrile (5.5 ml) was heated to 80 ⁰C for 30 minutes and then for one hour at 25-30 ⁰C. The solid was filtered and dried to obtain 0.7 g of title compound having purity of 99.52% by HPLC containing 0.08% R-enantiomer. Method B: A mixture of duloxetine hydrochloride (5 g, HPLC purity: 93.89% containing 7% R- enantiomer) in acetonitrile (35 ml) was heated to reflux to clear solution, followed by stirring at 25- 30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 3.1 g of title compound having purity of 99.7% by HPLC containing 0.11% R-enantiomer. Example 28: Preparation of duloxetine hydrochloride (I) Preparation of duloxetine oxalate

Duloxetine free base (2.5 g, HPLC purity: 90%) was dissolved in ethyl acetate (10 ml) and then solution of oxalic acid (1.1 g) in ethyl acetate (15 ml) was added. Stirred for one hour at 25-30 ⁰C. Filtered and dried the solid to obtain 3 g of duloxetine oxalate. (II) Preparation of duloxetine hydrochloride

A solution of duloxetine oxalate (3 g) and pyridine hydrochloride (2 g) in methanol (10 ml) was refluxed for 5 hours and cooled to room temperature. Methanol was distilled off in vacuum. Water (9 ml) and dichloromethane (20 ml) were added to the above solution and stirred for 30 minutes. The organic layer was separated, washed with water and concentrated in vacuum to obtain 2.2 g of title compound having purity of 96.80% by HPLC containing 7% R-enantiomer. (Ill) Purification of duloxetine hydrochloride

A mixture of duloxetine hydrochloride (2 g, containing 7% R-enantiomer) in acetonitrile (12 ml) was heated to reflux to clear solution, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 1.3 g of title ^compound having purity of 99.7% by HPLC containing 0.10% R-enantiomer.

Example 29: Preparation of duloxetine hydrochloride

(I) Preparation of duloxetine fumarate:

Duloxetine free base (23.0 g, HPLC purity: 90.12%) was dissolved in ethanol (46 ml) and then a solution of fumaric acid (9.0 g) in ethanol (69 ml) was added and the reaction mixture was stirred for one hour at 25-30 ⁰C. The reaction mixture was filtered and dried the solid to obtain 25.0 g of duloxetine fumarate having purity of 98.5% by HPLC. (II)Preparation of duloxetine hydrochloride:

A mixture of duloxetine fumarate (25.0 g), prepared above, in water (27 ml), 2N hydrochloric acid (54 ml) and dichloromethane (135 ml) was stirred for half hour. The organic layer was separated and washed with brine. Organic layer was concentrated in vacuum to obtain 18.0 g of title compound having purity of 99.0% by HPLC containing 7.58% R-enantiomer. (III)Purification of duloxetine hydrochloride The resulting compound (6 g, containing 7.58% R-enantiomer) in acetonitrile (35 ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 3.9 g of title compound having purity of 99.7% by HPLC containing 0.13% R-enantiomer. Example 30: Purification of duloxetine hydrochloride

A mixture of duloxetine hydrochloride (18.5 g containing 2.95% R-enantiomer) in acetonitrile (129 ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30 ⁰C for 3 hours. Then solid was filtered and dried in a vacuum oven, to obtain 13.0 g of title compound, having purity of 99.86% by HPLC containing 0.03% R-enantiomer. Example 31: Preparation of duloxetine hydrochloride

A solution of (S)-(+)-AζN-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (25 g) in toluene (125 ml) was heated to reflux and azeotroped under stirring for one hour. The temperature was lowered to 35-40 ^QC, diisopropylethylamine (11.4 g) followed by phenylchloroformate (18.85 g) were added and stirred at 30-35 ⁰C for one hour. The reaction mixture was washed with IN hydrochloric acid (50 ml), demineralized water (50 ml), 5% ammonium hydroxide (50 ml) and finally with demineralized water (50 ml). Toluene was distilled off under reduced pressure to obtain (S)-(+)-[N-methyl-[3-(l-naphthalenyloxy)-3-(2-thienyl)propyl]carbamic acid]phenyl ester. This compound was added to a pre-azeotroped suspension of potassium hydroxide (13.5 g) in toluene (168 ml) and again refluxed and azeotroped for 2 hours. The reaction mass was cooled to 25-30 ⁰C and washed with water. The organic layer was extracted with hydrochloric acid. The above hydrochloric acid solution was further extracted with dichloromethane. The dichloromethane solution was concentrated in vacuum to obtain 23 g of title compound having purity of 93.17% by HPLC containing 7% R-enantiomer. Example 32: Purification of duloxetine hydrochloride A mixture of duloxetine hydrochloride (23.0 g, HPLC purity: 93.17% and containing 7% R- enantiomer), in ethyl acetate (125 ml) was heated to 80 ⁰C for 30 minutes and then for one hour at 25-30 ⁰C. The solid was filtered and dried to obtain 19.0 g of title compound having purity of 98.49% by HPLC containing 4.92% R-enantiomer. The resulting compound (3.9 g) was heated in acetonitrile (27 ml) to reflux to obtain clear solution, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 2.9 g of title compound having purity of 99.70% by HPLC containing 0.11% R-enantiomer. Example 33: Preparation of duloxetine hydrochloride

A solution of (S)-(+)-N,iV-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine (75 g) in toluene (375 ml) was heated to reflux and azeotroped under stirring for one hour. The temperature was lowered to 35-40 °C, diisopropylethylamine (34.2 g) followed by phenylchloroformate (56.6 g) were added and stirred at 30-35 ⁰C for one hour. The reaction mixture was washed with IN hydrochloric acid (150 ml), demineralized water (150 ml), 5% ammonium hydroxide (150 ml) and finally with demineralized water (150 ml). Toluene was distilled off under reduced pressure to obtain (S)-(+)-[7V-methyl-[3-(l-naphthalenyloxy)-3-(2-thienyl)propyl]carbamic acid] phenyl ester. This compound was added to a pre-azeotroped suspension of potassium hydroxide (54 g) in toluene (500 ml) and again refluxed and azeotroped for 2 hours. The reaction mixture was cooled to 25-30 ⁰C and washed with water. The organic layer was extracted with hydrochloric acid. The above hydrochloric acid solution was extracted further with dichloromethane. The dichloromethane solution was concentrated in vacuum to obtain 68.3 g of title compound having purity of 91.32% by HPLC containing 7.2% R-enantiomer. Example 34: Purification of duloxetine hydrochloride

A mixture of duloxetine hydrochloride (3.2 g, HPLC purity: 91.32% containing 7.2% R-enantiomer) in acetonitrile (22 ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered and dried in a vacuum oven to obtain 2.4 g of title compound having purity of 99.60% by HPLC containing 0.12% R-enantiomer. Example 35: Purification of duloxetine hydrochloride

The mother liquor of examples 30, 32 and 34 was concentrated to obtain impure duloxetine hydrochloride containing 22% R-enantiomer. A mixture of this impure duloxetine hydrochloride (6.0 g), in acetonitrile (24 ml) was heated to reflux to obtain clear solution, followed by stirring at 25-30 ⁰C for 3 hours. Then solid was filtered and dried in a vacuum to obtain 1.8 g of title compound having purity of 99.02% by HPLC containing 0.7% R-enantiomer. Example 36: Purification of duloxetine hydrochloride

A mixture of duloxetine hydrochloride (0.5 g, containing 21% R-enantiomer, synthetically prepared by adding racemic duloxetine hydrochloride) in acetonitrile (2 ml) was heated to reflux, followed by stirring at 25-30 ⁰C for 3 hours. The solid was filtered, washed with acetonitrile (0.5 ml) and dried in a vacuum oven to obtain 0.2 g of title compound (containing 0.35 % R-enantiomer).

Claims

WE CLAIM:

1) A process for the preparation of duloxetine or pharmaceutically acceptable salt thereof, comprising a) condensing the 3-O-protected propanolamine derivative of formula III,

Formula III wherein R can be selected from straight chain or branched Cue alkyl, cycloalkyl, alkenyl, aϊkynyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, aminoalkyl or aminoaryl or heterocyclic ring with one or more hetero atom selected from nitrogen, oxygen or sulphur with 1-halonaphthalene in the presence of suitable base in an organic solvent to form N,N- dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine of formula II or acid addition salts thereof;

Formula II b) optionally, purifying the compound of formula II and acid addition salts thereof; and c) converting the compound of formula II or acid addition salt thereof to duloxetine or pharmaceutically acceptable salt thereof.

2) The process according to claim 1, wherein in step a) organic solvent includes halogenated hydrocarbons, ethers, aromatic hydrocarbons, esters, nitriles, dimethylsulfoxide, dimethylformamide, dimethylacetamide, iV-methyl pyrrolidine and the like. 3) The process according to claim 1, wherein in step a) suitable base includes tertiary alkyl amine such as triethylamine; alkali metal hydroxide, carbonates, bicarbonates thereof such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. 4) The process according to claim 1, wherein condensation reaction is optionally canied out in presence of phase transfer catalyst. 5) The process according to claim 4, phase transfer catalyst is selected from crown ethers, quaternary ammonium salts, quaternary phosphonium salt, or synthetic resins such as benzyltriethylammonium halide, tetrabutylammonium halide, 18-crown-6 and the like t>) ine process according to claim 1, wherein 1-halonaphthalene is selected from 1- chloronaphthalene, 1-bromonaphthalene, 1-fluoronaphthalene or 1-iodonaphthalene.

7) The process according to claim 1, (S)-duloxetine or pharmaceutically acceptable salt is prepared from (S)-isomer of 3 -0-protected propanolamine derivative of formula III. 8) The process according to claim 1, wherein 3-O-protected propanolamine derivative of formula

III is prepared by reacting the compound of formula IV

Formula IV with a reactive derivative of an acid.

9) The process according to claim 8, wherein reactive derivative of an acid include aryl carboxylic acid chloride; alkyl or aryl carboxylic acid anhydride; mixed anhydride and the like.

10) The process according to claim 8, wherein reactive derivative of an acid is selecetd from acetyl chloride, propionic acid chloride, butyric acid chloride, benzoyl chloride, acetic anhydride, butyric anhydride, propionic anhydride, ethyl methyl anhydride.

11) The process according to claim 8, further comprises resolving the racemic 3-Oprotected propanolamine derivative of formula III with a suitable resolving agent.

12) The process according to claim 11, suitable resolving agent is selected from tartaric acid, camphor sulfonic acid, camphoric acid, N-protected amino acids, mandelic acid, malic acid, tartaric acid, diaryl tartaric acid, di-p-tolyl tartaric acid, O,O'-dibenzoyltartaric acid, glucuronic acid, naproxen or ascorbic acid and the like, preferably di-p-tolyl tartaric acid. 13) The process according to claim 8, wherein (S)-isomer 3-O-protected propanolamine derivative of formula III is prepared from (S)-isomer of compound of formula IV. 14) The process according to claim 8, wherein compound of formula IV is prepared by a) reacting 2-acetylthiophene with N,iV-dimethylamine or acid addition salt thereof in presence of paraformaldehyde in a suitable solvent to give compound of formula V or acid addition salt thereof;

Formula V b) optionally, purifying the compound of formula V or acid addition salts thereof with a suitable solvent; and c) reducing the compound of formula V or acid addition salts thereof in presence of suitable reducing agent to form compound of formula IV. 15) The process according to claim 14, wherein in step a) suitable solvent includes alcoholic solvent, such as isopropyl alcohol, ethanol and the like.

16) The process according to claim 14, wherein in step b) suitable reducing agent include alkali metal hydride such as sodium borohydride, potassium borohydride, lithium borohydride and the like.

17) The process according to claim 14, wherein in step c) suitable solvent selected from nitriles; mixture of nitriles with alcohols, ketones and water.

18) The process according to claim 14, wherein in step c) suitable solvent is selected from acetonitrile,, aqueous nitrile. 19) The process according to claim 14, further involves the resolution of compound of formula IV with a suitable reducing agent.

20) The process according to claim 19, wherein suitable reducing agent is selected from mandelic acid, tartaric acid, camphor sulfonic acid, malic acid, camphoric acid, diaryl tartaric acid, di-p- tolyl tartaric acid, (9,0-dibenzoyltartaric acid, glucuronic acid, naproxen or ascorbic acid and the like, preferably mandelic acid.

21) The process according to claim 1, wherein compound of foπnula II is purified by acid base treatment.

22) A process for the preparation of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine of formula II or acid addition salts thereof, comprising a) condensing the 3-<9-protected propanolamine derivative of formula III with 1-halonaphthalene in the presence of suitable base in an organic solvent to form compound of formula II or acid addition salts thereof, and b) optionally, purifying the N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine of formula I or acid addition salts thereof. 23) The process according to claim 22, wherein in step a) organic solvent include halogenated hydrocarbons, ethers, aromatic hydrocarbons, esters, nitriles, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl pyrrolidine and the like.

24) The process according to claim 22, wherein in step a) suitable base includes tertiary alkyl amine such as triethylamine; alkali metal hydroxide, carbonates, bicarbonates thereof such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

25) The process according to claim 22, wherein condensation reaction is optionally earned out in presence of phase transfer catalyst. 26) The process according to claim 25, wherein phase transfer catalyst is selected from crown ethers, quaternary ammonium salts, and quaternary phosphonium salt or synthetic resins such as benzyltriethylammonium halide, tetrabutylammonium halide, 18-crown-6 and the like.

27) The process according to claim 22, wherein 1-halonaphthalene is selected from 1- chloronaphthalene, 1-bromonaphthalene, 1-fluoronaphthalene or 1-iodonaphthalene.

28) The process according to claim 22, wherein the compound of formula II is purified by acid base treatment.

29) A process for the preparation of highly pure duloxetine hydrochloride of formula I,

-HCl Formula I comprising: a) treating duloxetine with suitable acid to prepare duloxetine acid addition salt, b) converting duloxetine acid addition salt to duloxetine hydrochloride, and c) purifying duloxetine hydrochloride.

30) The process according to claim 29, wherein in step a) suitable acid is selected from organic acid or inorganic acid.

31) The process according to claim 29, wherein organic acid is selected from C_1-1O aliphatic carboxylic acid, aryl carboxylic acid, hetero-aryl carboxylic acid, aryl alkyl carboxylic acid and the like.

32) The process according to claim 30, wherein organic acid is oxalic acid, citric acid, maleic acid, formic acid, fumaric acid, acetic acid and the like.

33) The process according to claim 29, wherein inorganic acid is selected from hydrobromic acid, hydroiodic acid and the like.

34) The process according to claim 29, wherein in step b) duloxetine acid addition salt is converted to duloxetine hydrochloride by treating duloxetine acid addition salt with hydrochloride salt of base in presence of a protic solvent.

35) The process according to claim 34, wherein base is selected from ammonia, N₅N- dimethylamine, pyridine and the like.

36) The process according to claim 34, wherein protic solvent is selected from water and C_1-6 alcohol the like. 37) The process according to claim 34, wherein protic solvent is methanol or ethanol. oo; me process according to claim 29, wherein step b) duloxetine acid addition salt is converted to duloxetine hydrochloride by treating duloxetine acid addition salt with hydrochloric acid.

39) The process according to claim 29, wherein step c) duloxetine hydrochloride is purified using a nitrile solvent or a mixture of nitrile solvent with other suitable organic solvent. 40) The process according to claim 39, wherein the nitrile solvent is selected from C_1-5 alkylnitrile.

41) The process according to claim 40, wherein nitrile solvent is preferably acetonitrile.

42) The process according to claim 39, wherein other suitable organic solvent is selected from a C_2-8 ether, a C_5-8 aliphatic or C_6-12 aromatic hydrocarbon, C_1-8 ester C_3-10 ketone and halogenated hydrocarbons, straight chain or branched C_1-8 aliphatic alcohol, tetrahydrofuran, dimethylsulfoxide, dimethylforamide, iV-methylpyrrolidine, sulfolane.

43) A process for the purification of duloxetine hydrochloride of formula I comprising: a) heating crude duloxetine hydrochloride containing R-enantiomer in a nitrile solvent or in a mixture of nitrile solvent with other suitable organic solvent to obtain clear solution; b) cooling the reaction mixture, c) isolating pure duloxetine hydrochloride by filtration.

44) The process according to claim 43, wherein the nitrile solvent is selected from Ci_-5 alkylnitrile.

45) The process according to claim 43, where nitrile solvent is acetonitrile.

46) The process according to claim 43, wherein the suitable organic solvent is selected from a C_2-8 ether, a C_5-8 aliphatic or C_6-I2 aromatic hydrocarbon, C_1-8 ester C_3-1O ketone and halogenated hydrocarbons, straight chain or branched Ci_-8 aliphatic alcohol, tetrahydrofuran, dimethylsulfoxide, dimethylforamide, iV-methylpyrrolidine, and sulfolane.