FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
'PROCESS FOR THE PREPARATION OF DULOXET1NE HYDROCHLORIDE"
2. APPLICANT:
(a) NAME: IPCA LABORATORIES LTD.
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-400 067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

Field of the invention:
The present invention relates to a process for preparation of compound of Formula-V or its pharmaceutically acceptable salts. Particularly, the invention relates to a process for recycling the undesired isomeric intermediate, and its use in the preparation of anti depressant drug, Duloxetine or its salts. The invention further relates to novel impurities in Duloxetine and Duloxetine substantially free of those impurities.
Background oflnvention:
Duloxetine is a dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine. It is used for the treatment of depression, pain management and stress urinary incontinence (SUI).
Duloxetine is the S-enantiomeric form, chemically designated as (S)-(+)--N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine, has the following formula and is supplied as hydrochloride salt.

Duloxetine and its preparation are disclosed in US patents; US4956388 and US5023269. US5362886 discloses preparation of Duloxetine hydrochloride by reacting 2-acetyl thiophene with paraformaldehyde and dimethylamine hydrochloride in the presence of concentrated HC1 to get 3-(Dimethylamino)-l-(thiophen-2-yl)-propan-l-onehydrochloride followed by its reduction with sodium borohydride to get racemic 3-(Dimethylamino)-l-(thiophen-2-yl)-propan-l-ol. The racemic compound is resolved using (S)-(+)-Mandelic acid in ethanol solvent to get the (S)-3-(Dimethylamino)-l-(thiophen-2-yi)propan-l -ol which is further converted into Duloxetine. In this preparation method of Duloxetine, S-isomer of 3-(Dimethylamino)-l-(thiophen-2-yl)-propan-l-ol is used whereas the (R) isomer of 3-(Dimethylamino)-l-(thiophen-2-yl)-propan-1-ol is having no significance, remains as such in the mother liquor and hence being wasted.

WO2004/031168 discloses resolution of racemic compound, 3-,N-methylamino-l- (2-thienyl)-1-propanol, using (-)-2,3:4,6-Di-0- isopropylidene-2-keto-L-gulonic acid to yield (S)-(-)-3-,N-methylamino- l-(2-thienyl)-l-propanol. Both these documents do not address the recycling/reuse of the undesired R-isomer of 3-(DimethyIamino)-1-(thiophen-2-yl) propan-1-ol. The undesired R-isomer of 3-(Dimethylamino)-l-(thiophen-2-yl) propan-1-ol is discarded which is leading to disposal problems and effluent generation.
"Chirality in Industry II": by Collins, A. N., Sheldrake, G. M., Crosby, J., Eds.; John Willey & Sons: Chichester, 1997; pp 99-117 proposes a method for racemisation of the undesired R-enantiomer of 3-(Dimethylamino)-l-(thiophen-2-yl) propan-1-ol using methyl-t-butyl ether and HC1. The process described herein requires substantial work-up and the use of ether solvents make the process cumbersome.
In another PCT application, WO2007098250, racemization of undesired R-enantiomer of 3-(Dimethylamino)-i-(thiophen-2-y!)propan-l-oi, is mentioned. In said application, the undesired isomer is racemized in aqueous/organic solvents in presence of hydrochloric acid. However, the racemization process was found to be generating additional impurities that require additional purification for use of racemic product. Hence, the recovery of racemic product after racemization was found to be 30-35% only.
Consequently, if the use of R-isomer is made in the synthesis, it would result in great cost saving in the manufacturing of Duloxetine and a subsequent increase in the yield. Thus, there is a need to develop an economical and industrially applicable recycling process for converting the undesired (R)-3-(Dimethylamino)-l-(thiophen-2-yl)propan-l-ol into usable raw material with quantitative recovery and in satisfactory purity for further conversion of the obtained product into Duloxetine or its pharmaceutically acceptable salts.
Thus the objective of the present invention is to provide an economical and industrially applicable process, by overcoming the problems faced in the existing procedures, for preparing Duloxetine or its pharmaceutically acceptable salts in good quality and high yield.

Summary of Invention:
According to one aspect of the invention, there is provided a process for preparation of compound of Formula -V or its pharmaceutically acceptable salt thereof, wherein Rl denote H, linear or branched (C1 -C8)-alkyl, (C1 -C8)-acyl, cycloalkyl, aryl, comprising

Formula -V recycling of enantiomerically enriched R-isomer of Formula -III-B or salts thereof,

Formula-III B
wherein Rl and R2 independently of one another denote H, linear or branched (Cl-C8)-alkyl. (Cl-C8)-acyl, cycloalkyl, aryl, by first oxidizing it to obtain compound of Formula - II or its salt;

Formula - II wherein Rl and R2 have the meaning given above; and further reducing it to compound of Formula -III


Formula - III wherein R1 and R2 have the meaning given above, for use in the resolution and subsequent conversion into compound of Formula-V.
According to another aspect of the invention, there is provided a process for preparation of duloxetine or a pharmaceutically acceptable salt thereof comprising:

Duloxetine reacting enantiomerically enriched (R)-isomer of compound of formula-III-B or salts
thereof,
Formula - III B
Formula II
wherein R1 and R2 both are methyl, with an oxidizing agent to obtain compound of Formula - II, optionally converting the compound of Formula -II to its salt,


followed by conversion of the compound of formula -II into duloxetine or it's pharmaceutically acceptable salt.
According to yet another aspect of the invention, there is provided a process for preparation of compound of Formula-II, wherein R1 and R2 independently denote H, linear or branched (Cl-C8)-alkyl, (Cl-C8)-acyl, cycloalkyl, aryl, or its salt comprising oxidizing racemic or enantiomers of compound of Formula -III, wherein Rl and R2 have the meaning given above, with a suitable oxidizing agent and optionally converting the obtained compound into its salt.

In a preferred embodiment of the present invention, the oxidation reaction is performed in the presence of a suitable solvent.
According to further aspect, the invention relates to novel impurities of Formula -VII and Formula-VIII and Duloxetine substantially free from these compounds.

Formula -VII Formula-VIII
Detailed description of the invention:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Enantiomerically enriched R-isomer means the isomer ratio of R:S varies from 51:49 to 100:0, for example 70:30 :: R-isomer:S-isomer.
Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
In an embodiment, the invention provides an economical and novel process to prepare compound of Formula -V or its pharmaceutical!)' acceptable salt, wherein Rl denote H, linear or branched (Cl-C8)-alkyl, (Cl-C8)-acyl, cycloalkyl, aryl, however, Rl which denotes methyl is preferred, by recycling the undesired enantiomerically enriched R-isomer of Formula-III-B, wherein Rl and R2 independently of one another denote H, linear or branched (C1-C8)-alkyl, (Cl-C8)-acyl, cycloalkyl, aryl, by subjecting it for oxidation and further conversion into compound of Formula -V. The compound of Formula V is preferably Duloxetine.
In a preferred embodiment of the present invention, both Rl and R2 are methyl.
Although, the invention is exemplified to recycling of R-isomer, it will be appreciated in the art that the invention includes oxidation of racemic or the enantiomers, which are obvious variants of the invention.
The following scheme illustrates the invention.


Rl and R2 as defined above
Thus according to preferred embodiment of the present invention, there is a process provided for preparation of Formula-II or its salt, wherein both Rl and R2 are methyl, comprising reacting compound of formula-III-B, wherein both Rl and R2 are methyl, with a suitable oxidizing agent and optionally converting the obtained compound of Formula -II into its salt.
The oxidizing agent is selected from Manganese dioxide (MnO2), potassium permanganate (KMn04), Sodium hypobromite (NaOBr), Sodium hypochlorite (NaOCl), Ruthenium tetroxide (RuCU), chromic acid in sulfuric acid, dipyridine, Cr(VI) oxide, pyridinium chlrochromate, hydrogen peroxide (H2O2), H2O2-molybdate,' RuCl2(PPh3)3 and Osmium Tetroxide. MnC>2 is most preferred oxidizing agent. During reaction, the oxidizing agent may be used in molar proportion or in excess to the substrate. Typically molar ratio is used in the range of 1.2 to 5 mole of oxidizing agent per mole of substrate.
In a preferred embodiment, the oxidation process is carried out in a solvent medium.
The solvent medium includes, but not limited to, aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, esters, ethers, ketones, polar aprotic solvents, nitriles etc.

Chlorinated hydrocarbons preferably include methylene dichloride, ethylene dichloride, chloroform, carbontetrachloride, and aromatic hydrocarbons preferably selected from toluene, xylene, and aliphatic hydrocarbons include hexane, cyclohexane, heptane etc. Esters include ethyl acetate or butyl acetate. Ethers include tetrahydrofuran, dioxane, ethyl ether or methyl -t-butyl ether. Polar aprotic solvents include DMSO or DMF. Preferred solvent is chloroform.
The reaction may be performed at temperatures varying from 0°C to reflux temperature of solvent used. The time taken for completion of the reaction varies from 2 hours to about 40 hours.
After completion of reaction, the compound of Formula-II is isolated by conventional procedures such as filtration of byproducts or separation of layers followed by distillation of solvent.
The compound of Formula -11 may be directly used for further reaction, or may be purified, optionally by forming salt with organic/inorganic acids such as HCI, H2SO4, phosphoric acid; preferably HCl.
Preferred solvents for making the salt are selected from, but not limited to, alcohols, especially isopropyl alcohol.
In yet another embodiment, the compound of Formula-II or its salt (Formula -II -A) prepared in any of the above processes may subsequently be converted into Duloxetine or its pharmaceutically acceptable salt.
The process for conversion to compound of Formula -V, wherein Rl is methyl, from compound of Formula-II, wherein both Rl and R2 are methyl, is illustrated as follows.
Accordingly, in one method, the conversion comprises reacting compound of Formula-II -A , wherein both Rl and R2 are methyl, with a reducing agent such as metal hydride complex in methanol solvent in the presence of aqueous NaOH at ambient temperature. Alternately reduction can also be performed using hydrogen in the presence of suitable metal catalysts, such as palladium, platinum, ruthenium, rhodium and nickel in alcohol solvent. Suitable metal hydride complex include sodium borohydride, lithium

borohydride and lithium aluminium hydride. Preferred reducing agent is sodium borohydride. After completion of reaction, product of Formula-Ill is isolated by conventional methods such as distillation of methanol followed by extraction.
The compound of Formula - III can be converted into Duloxetine, compound of Formula -V, wherein Rl is methyl, by any method known to person of ordinary skill in the art. In one method, the compound of Formula - 111 is resolved; the obtained desired S-isomer of Formula-III-A is condensed with l -fluoronaphthalene followed by demethylation to get Duloxetine.
In another method, the racemic compound of Formula- III is condensed with 1-fluoronaphthalene followed by demethylation and then performing resolution to get Duloxetine.
In a preferred embodiment of the present invention, the resolution of the compound of Formula -III is performed using a chiral acid to obtain S-isomer of Formula III -A in a suitable solvent medium.
The chiral acid can typically be selected from the group consisting of mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid, bisnaphthylphosphoric acid and the like. Most preferred chiral acid is (S)(+)Mandelic acid.
The suitable solvent medium includes water; alcohols such as methanol, ethanol, 1-propanol and 2-propanol; ethers such as diethyl ether, methyl tert-butyl ether and tetrahydrofuran; acetic acid; esters such as methyl acetate, ethyl acetate; isopropyl .acetate and butyl acetate; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; nitriles such as acetonitrile; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dich!oroethane; and aromatic hydrocarbons such as benzene, toluene and xylenes. The solvents may be used solely or in combination of two or more of them; Preferred solvent is mixture of ethanol and t-butyl methyl ether. The diasteriomerically enriched salt of S-isomer of Formula -III A-mandelate is filtered and subjected for Duloxetine preparation.
Whereas, the enriched R-isomer of Formula -III B present in the filtrate is isolated by distilling the solvent. The isolated R-isomer is then subjected for recycling. R-isomer may

be pure or contaminated with S-isomer also. The obtained R-isomer of Formula -III B is subjected for oxidation as per the invention mentioned above.
The S-isomer of Formula -IIIA-mandelate diasteromeric salt is dissolved in water at room temperature followed by addition of aqueous NaOH; maintaining pH 10 -12; to liberate the free base of Formula-III-A. The free base of Formula -III-A is then isolated by conventional methods such as extracting with a water immiscible solvent such as methylene dichloride (MDC) followed by distillation of the solvent.
Further, the compound of Formula -III-A is treated with NaH in DMSO followed by reaction with 1-fluoro naphthalene at 50-55°C. After completion of reaction, the reaction mixture was cooled to isolate compound of Formula-IV.
In an embodiment, the invention relates to novel impurities of Formula -VII and Formula-VIII and Duloxetine substantially free from these impurities. The impurities of formula VII and VIII are formed during the demethylation of compound of formula IV using phenyl chloroformate. Subsequently the impurities are isolated from the reaction mass and characterized.

Formula-VII Formula-VIII
Further, the inventors have surprisingly found an improved process for preparing duloxetine or its salts substantially free from these impurities of Formula -VII and VIII by demethylation of compound of Formula-IV.
In an embodiment the impurities of Formula VII and formula VIII are characterized by IR, Mass spectrometry, PMR and CMR and are mentioned below.

a) Characterization of Compound of Formula-VH
Chemical Name: N-methyl-N-phenoxycarbonyl-(3-(l-naphthalenoxy, 2-hydroxy)-3-
(thien-2-yl) propylamine
IR (KBR) : 3288 cm-], 2924 cm-1, 1594 cm-1, 1574 cm-1, 1466cm-l, , 809 cm-1, 749 cm-1
MASS:
(M-1):4I6
Sample : DLX Carb imp
Instrument : BRUKER 400MHz
Solvent : DMSO-d6
Experiment : PROTON NMR
Structure*:

Interpretation:

Chemical shift value (5/ppm) Assignment
(multiplicity", number of proton, position*)
2.30-2.45 (m,2H,12)
2.93 & 3.04 (2xs,3H,25)
3.16-3.31 (m,2H,13)
5.00-5.08 (m,1H,11)
6.90-6.7.47 (m, 12H, 1,2,7.8,16,17,18,19,20,22,23,24)
7.81-7.83 (m,1H,3)
8,27-8.29 (m,lH,6)
9.49-9.53 (2xs,lH,26)

# s- singlet, m-multiplet.
Sample : DLX Carb imp
Instrument : BRUKER 400MHz
Solvent : CDC13
Experiment : l3C NMR
Structure*:

Interpretation;

Chemical shift value (8/ppm) Assignment (position*)
133.48 5
120.29 8
149.23 9
47.68,48.13 11
34.73,34.41 12
35.79, 36.08 13
154.19 14
151.71 15
124.29 16,20
129.60 17, 19
148.95, 149.09 21
34.92 25
122.25,122.36,122.68,125.34, 125.43, 125.47, 125.80, 126.10, 127.98 1,2,3,4,6,7,10,18,22,23,24

Note: The given sample exhibit isomeric pattern in 13C NMR spectra.
b) Characterization of Compound of Formula -VIII
Chemical Name: N-methyi-N-phenoxycarbonyl-(3-(I-naphthalenoxy, 4-hydroxy)-3-(thien-2-yl) propylamine
IR(KBR): 3318 cm-1, 2925 cm-l, 1696 cm-1, 1624 cm-1, 1586 cm-l, 1517 cm-1, 828 cm-1, 753 cm-1
MASS :
(M-l):416
Sample : DLX Carb imp
Instrument : BRUKER 400MHz
Solvent : CDCl3
Experiment : PROTON NMR
Structure*:


Interpretation:

Chemical shift value (5/ppm) Assignment
(multiplicity#, number of proton, position*)
2.53-2.63 (m,2H,12)
2.99-3.06 (2 x s,3H,25)
3.36-3.56 (m,2H,13)
4.93-5,00 (m,IH,II)
6.09-6,16 (2xs,!H,26)
6.94-6.73 (t,lH,8)
6.88-6.92 (m,2H,18&23)
7.01-7,03 (d,lH,16)
7.10-7,21 (m,3H,20,22&24)
7.28-7.38 (m,3H,9,17&19)
7.43-7.52 (m,2H,l &2)
8.04-8.08 (m,lH,6)
8.23-8.27 (m,lH,3)
# s- singlet, t- triplet, d-doublet, m-multiplet.
Sample : DLX Carb imp
Instrument : BRU KER 400MHz
Solvent : CDC13
Experiment : 13C NMR
Structure*:


Interpretation:

Chemical shift value (S/ppm) Assignment (position*) Chemical shift value (8/ppm) Assignment (position*)
126.60, 126-73 f 151.25 14
124.66, 124.81 2 150.97, 150.99 15
122.65, 122.69 3 121.60 16
124.95, 124.97 4 124.17 17
132.35 5 124.23 18
122.84, 122.95 6 124.30 19
154.85, 154.91 7 121.75 20
107.98, 108.04 8 148.79, 149.13 21
129.19, 129.23 9 125.20, 125.27 22
131.08 10 126.57 23
38.72, 38.96 11 123.49, 123.64 24
34.7, 25.6 12 35.02, 35.20 25
48.18,48.66 13 - 26
Accordingjy, the compound of formula-IV is reacted with phenyl chloroformate in toluene solvent in the presence of diisopropylethylamine for a period of 14-18 hours at 55-60°C till completion of the reaction. The reaction mass is then quenched in water, separated the layers and the organic layer is washed with 10% sodium hydroxide solution to obtain carbamate (Carbamic acid, N-methyl-N-[(3S)-3-(l-naphthalenyloxy)-3-(2-thienyfjpropyl]-, phenyl ester)as oil. Formation of impurity of Formula -VII varies in the range of 1- 3% and Formula -VIII varies between 0-1% by HPLC.
Similar demethylation procedure can also be applied to racemic compound of Formula-IV.
The obtained carbamate is further reacted with aqueous NaOH in dimethylsulfoxide to get Duloxetine base of Formula -V. Duloxetine base is converted to its pharmaceutically

acceptable salt, preferably HCI, by reacting with HC1 in ethylacetate solvent to obtain Duloxetine hydrochloride of Formula -VI.
The Duloxetine HCI obtained by the process of the present invention, may be formulated into a suitable dosage form such as tablets, capsules, etc., by combining with one or more pharmaceutically acceptable excipients using known techniques. The dosage form may include a suitable amount of the active ingredient and other pharmaceutical agents. The dosage forms prepared by the process of the present invention may be administered to a mammal in need, for the treatment of depression, pain management and stress urinary incontinence (SUl).
The following examples, which include preferred embodiments, is intended to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Example 1: Preparation of 3-(Dimethylamino)-l-(thiophen-2-yl)-propan-l-one, Hydrochloride
250g (1.98mol) 2-acetyl thiophene, 203.4g (2.49mol) dimethyl amine hydrochloride and 88.5g (2.95 mol) Para formaldehyde were added in isopropyl alcohol (600 mi). The mixture was stirred at room temperature for 15 minutes and 9.6g (0.26 mol) concentrated hydrochloric acid was added to this reaction mixture. Heated the reaction mass to reflux and maintained the reflux for 15 hours. After completion of reaction, the mixture was cooled to room temperature and then to 0°C. Stirred the mixture at this temperature for one hour. The precipitated solid was filtered and washed with cold isopropyl alcohol and dried the product under vacuum at 50°C to obtain 399.5g (91.7%) of title compound as a white crystalline solid. HPLC> 99.5 %, Melting point 181.9-182.6 °C.
Example 2: Preparation of 3-(Dimethylamino)-l-(thiophen-2-yl)-propan-l-ol
350 g (1.594 mol) of 3-(Dimethylamino)-l-(thiophen-2-yl)-propan-l-one was added to 1160 ml of methanol at room temperature. The mixture was stirred at room temperature for 30 minutes. The pH of the reaction mass was adjusted to basic by using 20% aqueous sodium hydroxide at room temperature. 30. lg (0.796 mol) sodium borohydride was added

to the above mixture portion wise over a period of 30 minutes. The reaction mass was stirred for 2-3 hours at room temperature. After completion of reaction, the reaction mass was distilled to remove methanol and extracted with 350 ml methylene dichloride. The MDC layer and aqueous layer were separated.
The aqueous layer was further extracted with methylene dichloride (100ml x 3). The methylene dichloride extracts were combined, dried over sodium sulphate and filtered. The obtained filtrate was concentrated under reduced pressure to obtain 280 g (95%) of the title compound.
HPLC > 97%, Melting point 68-71 °C.
Example 3a: Preparation of (S)-3-(Dimethylamino)-l-(thiophen-2-yl)-propan-l-ol.
250 g (1.35mol) of 3-(Dimethylamino)-l-(thiophen-2-yl)-propan-l-ol was added in 1500 ml t-butyl methyl ether at room temperature. The mixture was heated to reflux to get clear solution. Meanwhile prepared the solution of (S) - (+)- mandelic acid (102.6 g (0.674 mol) in 300 ml of ethanol. (S)-(+)- Mandeiic acid solution was added drop wise at reflux temperature to the above reaction mass over a period of 3-4 hours.
Maintain the reflux further for 1-2 hour. The reaction mixture was cooled to room temperature and stirred for 1 hour. The obtained precipitate was filtered and washed the product with t- butyl methyl ether ,The obtained solid was dried under vacuum at 50°C for 6 hours to get mandelate salt of 3-(Dimethylamino)-l-(thiophen-2-yl)-propan-l-ol. 207.5 g ,(45.6%).HPLC Chiral purity > 98%, Melting point-122.7°C (lit. 121-24°C). SOR:(+) 310 (c=l, Methanol).
The above mandelate salt (200 g, 0.592 mol) was dissolved in 1320 ml of water at room temperature. The pH of reaction mass was adjusted to 10 by using aqueous 10 % sodium hydroxide (250ml),Stirred the mixture at this pH for 1 hour at room temperature. The reaction mass was extracted with methylene dichloride twice. The combined organic layer was washed with water and dried over sodium sulphate. Distilled out methylene dichloride under reduced pressure to get 105g of the title compound. Chiral purity: 99.46%, melting point 72°C (lit 70-80°C), SOR (-) 6.59 (c=l, Methanol),lit. (-) 6.2.

Example 3b: Preparation of 3-(Dimethylamino)-l-(thiophen-2-yl)-propan-l-one, Hydrochloride: (OXIDATION OF R- ISOMER)
125 g (0.67mol) of above R- isomer of 3-(Dimethy[amino)-l-(thiophen-2-yl)-propan-l-ol was taken in 600 ml of chloroform. To this solution 225,2 g (2.59 mol) manganese dioxide was added at room temperature. The obtained mixture was refluxed for 30 hours. After completion of reaction, filtered the reaction mixture through celite. The filtrate was concentrated under reduced pressure and dried under vacuum. The obtained oily residue was dissolved in 300 ml of isopropyl alcohol. To the above reaction mass hydrochloric acid (54 g) was added over 1 hour. Cooled the reaction mixture to 0-5°C and stirred for 1 hour (0-5° C). The product was filtered and washed with cold isopropyl alcohol (50 ml x 2). The product was dried at 50°C under vacuum to obtain 943 g of title compound. HPLC: 99.20 %.
Example 4: Preparation of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyhpropanamine :
23.3g (0.582 mol) of 60% of sodium hydride was added in 150 ml of dimethyl sulfoxide at room temperature under N2. The mixture was stirred at room temperature for 30 minutes. To this, a solution of (S)-(-)-3-(Dimethylamino)-l-(thiophen-2-yl)-propan-l-ol (100 g,0.539 moi) in 350 ml of dimethyl sulfoxide was added at 30-40°C, followed by 85.2 g(0.582 mol) of 1-fluro naphthalene in 100 ml of dimethyl sulfoxide at 55-60°C over I hour. The obtained mixture was stirred at same temperature for 15 hours. After the completion of reaction, the reaction mixture was cooled to room temperature. Reaction mixture was poured in 1200 ml of water, stirred for 30 minutes and then cooled to 0-5°C. The pH of the reaction mass was adjusted to 1.5 by using conc, hydrochloric acid. The mixture was extracted with n-hexane (100 ml x 2).The pH of the aqueous layer was adjusted to 11-12 using 20% sodium hydroxide, and extracted twice with toluene. The combined toluene layer was washed with water, dried over sodium sulphate and filtered. The obtained filtrate concentrated to obtain 152g (90.3%) of title compound as brown oil. HPLC>97%.
Example 5: Preparation of Duloxetine hydrochloride
125 g (0.4mol) of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine was added in 1250 ml of toluene at room temperature under N2, and 26g

(0.22 mol) of diisopropylethylamine was added to this solution at room temperature. Reaction mass was heated to 55-60°C and 107g(0.68mol) of phenyl chloroform ate in 375 ml of toluene was added drop wise over 1 hour and maintained the reaction mass at 55-60°C for 15 hours. After completion of reaction, the reaction mass was cooled to room temperature, quenched in 1200 ml of water and cooled to 10-15°C. The reaction mass was extracted with toluene, and toluene layer washed with 10%sodium hydroxide solution. The combined toluene layer dried over sodium sulphate, filtered, and filtrate concentrated under vacuum at 45° C to obtain 192g of ((S)-N-methyl-[3-(l-naphthalen-l-yloxy)-3-thiophen-2-yl-propyl] carbamic acid phenyl ester) as brown oil,
HPLC: purity: 94.51%, impurity of Formula-VII: 1.73%, impurity of Formula-VIII: 0.02%
150 g (0.359 mol) of ((S)-N-methyl-[3-(1-naphthalen-l-yloxy)-3-thiophen-2-yl-propyl] carbamic acid phenyl ester) was then added in 750 ml of dimethyl sulfoxide at room temperature. The mixture was. stirred for 30 minutes to get clear solution. Reaction mixture was heated to 70-80°C. Sodium hydroxide (59.6 g dissolved in 300 ml of water) was added drop wise over 1 hour and maintained this temperature for 5 hours. After completion of reaction, the mass was cooled to room temperature. The reaction mass was quenched in 1500 ml of distilled water and stirred for 30 minutes at 10-15°C.The mixture was extracted with ethyl acetate (300 ml x 3). The combined ethyl acetate extract was dried over sodium sulphate and filtered. Filtrate was concentrated under reduced pressure and dried under vacuum. The obtained residue was dissolved in 300 ml of ethyl acetate followed by addition of hydrochloric acid in ethyl acetate (pH 1 -2), stirred the mass for 1 hour at 0-50C to get the precipitate.
The precipitate obtained was filtered and washed with 150 ml of ethyl acetate. The wet material was again dissolved in 300 ml of ethyl acetate. Stirred at 0-5X for one hour. The product was filtered and washed with cold ethyl acetate (150ml). Dried the product at 50-55°C under vacuum to obtain the titled compound (51.7 g). HPLC: 99.92%, Chiral purity: 99.7%, R-isomer 0.18%. SOR (+) 122.4(c=l, Methanol)

We claim;
1) A process for preparation of compound of Formula -V or a pharmaceutically acceptable salt thereof.

Formula-V
wherein Rl denote H, linear or branched (C1-C8)-alkyl, (Cl-C8)-acyl, cycloalkyl or aryl comprising:
a) reacting enantiomerically enriched (R)-isomer of compound of Formula-III-B or salts thereof,

Formula-III B
Formula - II
wherein Rl and R2 independently of one another denote H, linear or branched (C1-C8)-alkyl, (Cl-C8)-acyl, cycloalkyl or aryl, with an oxidizing agent to obtain compound of Formula - II;

Duloxetine a) reacting enantiomerically enriched (R)-isomer of compound of Formula-III-B or salts
'thereof,

Formula-III B
wherein Rl and R2 both are methyl, with an oxidizing agent to obtain compound of Formula - II;

Formula- II
b) optionally converting the compound of Formula -II to it's salt; and
c) converting the compound of Formula -11 into duloxetine or it's pharmaceutically acceptable salt.

3) The process as claimed in claim 1 or claim 2, wherein the oxidizing agent is selected
from manganese dioxide, potassium permanganate, sodium hypobromite, sodium
hypochlorite, ruthenium tetroxide, chromic acid in sulfuric acid, dipyridine Cr(VI) oxide,
pyridinium chlrochromate, hydrogen peroxide(H202), H202-molybdate, RuC12(PPh3)3
and Osmium Tetroxide.
4) The process as claimed in claim 1 or claim 2, wherein the reaction of step-a is performed in a suitable solvent medium.
5) The process as claimed in claim 4, wherein the solvent is selected from aliphatic hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, esters, ethers, ketones, polar aprotic solvents or nitriles, or mixtures thereof.
6) The process as claimed in claim 5, wherein the chlorinated hydrocarbon is methylene dichloride, ethylene dichloride or chloroform.
7) The process as claimed in claim 1 or claim2, wherein the reaction is performed at a temperature ranging from 0°C to reflux temperature of solvent used.
8) The process as claimed in claim 3, wherein the oxidizing agent is used in the range of 1.2 to 5 mole per mole of Formula-III B,
9) The process as claimed in claim 2, wherein the compound of Formula-II is converted to Duloxetine or it's pharmaceutically acceptable salt by a process comprising:

Formula- 111
a) reducing the compound of Formula -II or it's salt with a reducing agent such as sodium borohydride to obtain compound of formula-Ill, wherein Rl and R2 both are methyl;

b) resolving the compound of Formula -III, wherein Rl and R2 both are methyl, using a chiral acid such as S(+) Mandelic acid to obtain S-enantiomer of compound of formula-IIIA;

Formula-1I1A
c) condensing the compound of Formula-III A., wherein Rl and R2 both are methyl, with 1-fluoronaphthalene to form compound of Formula-IV;

Formula -IV
d) demethylating the obtained compound of Formula -IV, wherein Rl and R2 both are methyl, using phenyl chloroformate to get duloxetine or it's pharmaceutically acceptable
salt.
10) The process as claimed in claim 9, wherein the duloxetine pharmaceutically
acceptable salt is duloxetine hydrochloride.
11) A process for preparation of a compound of Formula-II,

Formula - II wherein Rl and R2 independently of one another denote H, linear or branched (C1-C8)-
alkyl, (Cl-C8)-acyl, cycloalkyl, aryl or it's salt comprising:

a) reacting racemic or enantiomers of compound of Formula -III,

Formula - 111
wherein Rl and R2 independently of one another denote H, linear or branched (C1-C8)-alkyl, (Cl-C8)-acyl, cycloalkyl, aryl, with an oxidizing agent to obtain compound of Formula-11 and,
b) optionally converting the obtained compound of Formula -II into it's salt.
12) The process as claimed in claim 11, wherein the oxidizing agent is selected from manganese dioxide, potassium permanganate, sodium hypobromite, sodium hypochlorite, ruthenium tetroxide, chromic acid in sulfuric acid, dipyridine Cr(VI) oxide, pyridinium chlrochromate, hydrogen peroxide(H202), H202-molybdate, RuCI2(PPh3)3 and Osmium Tetroxide.
13) The process as claimed in claim 11, wherein the reaction is performed in a suitable solvent medium.
14) The process as claimed in claim 13, wherein the solvent is aliphatic hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, esters, ethers, ketones, polar aprotic solvents, nitriles or mixtures thereof.
15) The process as claimed in claim 14, wherein the chlorinated hydrocarbon is
methylene dichloride, ethylene dichloride or chloroform.
16) The process as claimed in claim 11, wherein both Rl and R2 are methyl.
17) The process as claimed in claim 11, wherein the oxidizing agent is manganese
dioxide.

18) A compound of Formula -VII

Formula - VII
19) A compound of Formula -VIII

Formula - VIII
20) (S)-N-methyl-[3-(l-naphthaIen-l-yloxy)-3-thiophen-2-yl-propyl] carbamic acid phenyl ester (carbamate) having less than 2 percent of compound of Formula-VII and less than 0.1 percent of compound of Formula-VIII.