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Title:
AN IMPROVED PROCESS FOR THE PREPARATION OF DULOXETINE
Document Type and Number:
WIPO Patent Application WO/2006/126213
Kind Code:
A1
Abstract:
A process for preparing Duloxetine, or its acid addition salt, which process comprises (i) condensation of (S)-(-)-N, N-dimethyl-3-(2-thienyl)-3-hydroxy propanamine with 1-fluoronaphthalene followed by demethylation or condensation of N, N-dimethyl-3-(2-thienyl)-3-hydroxy propanamine with 1-fluoronaphthalene followed by resolution and demethylation; and (ii) if desired, converting Duloxetine to its acid addition salt.

Inventors:
SATYANARAYANA CHAVA (IN)
RAMANJANEYULU GORANTLA SEETA (IN)
RAMDAS CHAVAKULA (IN)
RAO KONUDULA BABU (IN)
Application Number:
PCT/IN2006/000174
Publication Date:
November 30, 2006
Filing Date:
May 23, 2006
Export Citation:
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Assignee:
MATRIX LAB LTD (IN)
SATYANARAYANA CHAVA (IN)
RAMANJANEYULU GORANTLA SEETA (IN)
RAMDAS CHAVAKULA (IN)
RAO KONUDULA BABU (IN)
International Classes:
C07D333/10
Domestic Patent References:
WO2006045255A12006-05-04
Foreign References:
US5362886A1994-11-08
Attorney, Agent or Firm:
Rao, Ramana Ch V. (Plot No. 38 Phase-IV, ID, Jeedimetla Hyderabad 5, IN)
Download PDF:
Claims:
We claim:
1. A process for the preparation of Duloxetine, or an acid addition salt comprising steps: a. Condensation of N, Ndimethyl3(2thienyl)3hydroxypropanamine with 1 fluoro naphthalene so as to obtain N, Ndimethyl3(lnaphthalenyloxy) 3(2 thienyl) propanamine (optionally converting it to its oxalate salt). b. Resolving the racemic N,Ndimethyl3(lnaphthalenyloxy)3(2thienyl) propanamine with a chiral acid so as to obtain a salt of the chiral acid and N,N dimethyl3(lnaphthalenyloxy)3(2thienyl) propanamine c. Demethylation of (S)(+)N,Ndimethyl3(lnaphthalenyloxy) 3(2thienyl) propanamine to get Duloxetine d. If desired, converting Duloxetine to its acid addition salt.
2. The process as claimed in claim 1, wherein the condensation is carried out in the presence of an alkoxide selected from potassium tertbutoxide, sodium methoxide and sodium ethoxide.
3. The process as claimed in claim 1, wherein the condensation is carried out in an organic polar solvent selected from Dimethyl sulphoxide, N,NDimethyl formamide and N,NDimethyl acetamide.
4. The process as claimed in claim 1, wherein the N,Ndimethyl3(lnaphthalenyloxy) 3(2thienyl) propanamine is isolated as its acid addition salt which includes oxalate salt, phosphate salt, hydrochloride salt, nitrate salt and tartrate salt.
5. The process as claimed in claim 1, wherein the resolution of N,Ndimethyl3(l naphthalenyloxy) 3(2thienyl) propanamine is carried out with a chiral acid selected from Tartaric acid, Mandelic acid, camphor sulphonic acid, Dibenzyl tartaric acid and Diparatolyl tartaric acid.
6. The process as claimed in claim 1, wherein the resolution of N,Ndimethyl3(l naphthalenyloxy) 3(2thienyl) propanamine is carried out in a solvent selected from alkanols, esters or a mixture of alkanol, ester and water.
7. The process as claimed in claim 1, wherein the demethylation takes place in presence of phenyl chloroformate.
8. The process as claimed in claim 1, wherein the preferable addition salt is hydrochloride.
9. A process for the preparation of Duloxetine, or an acid addition salt comprising steps: a. Condensing (S)()N, Ndimethyl3 (2thienyl)3hydroxy propanamine with 1 fiuoronaphthalene so as to obtain (S)(+)N, Ndimethyl3 (1naphthalenyloxy) 3(2thienyl) propanamine (optionally converting it to its oxalate salt). b. Demethylation of (S)(+)N, Ndimethyl3 (lnaphthalenyloxy)3(2thienyl) propanamine to get Duloxetine. c. If desired, converting Duloxetine to its acid addition salt as appropriate.
10. The process as claimed in claim 9, wherein the condensation is carried out in the presence of an alkoxide selected from potassium tert.butoxide, sodium methoxide and sodium ethoxide.
11. The process as claimed in claim 9, wherein the condensation is carried out in an organic polar solvent selected from Dimethyl sulphoxide, N,NDimethyl formamide and N,NDimethyl acetamide.
12. The process as claimed in claim 9, wherein the (S)(+)N, N~dimethyl3 (1 naphthalenyloxy)3(2thienyl) propanamine is isolated as its acid addition salt which includes oxalate salt, phosphate salt, hydrochloride salt, nitrate salt and tartrate salt.
13. The process as claimed in claim 9, wherein the demethylation takes place in presence of phenyl chloro formate.
14. The process as claimed in claim 1, wherein the preferable addition salt is hydrochloride.
15. A process for the preparation of Duloxetine, or an acid addition salt comprising steps: a. Racemization of the ()N,Ndimethyl3(lnaphthalenyloxy) 3(2thienyl) propanamine b. Resolution of the racemic N,Ndimethyl3( 1naphthalenyloxy) 3(2thienyl) propanamine and separating (S)(+)N, Ndimethyl3 (1naphthalenyloxy) 3(2 thienyl) propanamine c. Demethylation of the (S)(+)N, Ndimethyl3(lnaphthalenyloxy)3(2thienyl) propanamine to get Duloxetine d. If desired, converting Duloxetine to its acid addition salt as appropriate.
16. The process as claimed in claim 15, wherein the racemization of the ()N,N dimethy 13 (1naphthalenyloxy) 3(2thienyI) propanamine is carried out in a solvent solvent selected from alkanols or polar aprotic solvents.
17. The process as claimed in claim 15, wherein the employed ()N,Ndimethyl3(l naphthalenyloxy) 3(2thienyl) propanamine for racemization contains about 1% to 45% (+)N,Ndimethyl3( 1naphthalenyloxy) 3(2thienyl) propanamine.
18. The process as claimed in claim 15, wherein the racemization of the ()N,N dimethyl3( 1naphthalenyloxy) 3(2thienyl) propanamine is carried out in presence of a base selected from alkali metal hydroxides preferably potassium hydroxide.
19. The process as claimed in claim 15, wherein the resolution of N,Ndimethyl3(l naphthalenyloxy) 3(2thienyl) propanamine is carried out in a solvent selected from alkanols, esters or a mixture of alkanol, ester and water.
20. The process as claimed in claim 15, wherein the demethylation takes place in presence of phenyl chloroformate.
21. The process as claimed in claim 15, wherein the preferable addition salt is hydrochloride.
Description:
"An improved process for the preparation of Buloxetine"

The present invention relates to an improved process for the preparation of (S)-(+)-N, N- dimethyl-3- (1-naphthalenyloxy) -3-(2-thienyl) propanamine, a key intermediate for the preparation of Duloxetine or an acid addition salt.

Background of the Invention: Duloxetine, [(+)-N-methyl-3- (l-naphthalenyloxy)-3-(2-thienyl) propanamine] has the following structure

Duloxetine

Duloxetine hydrochloride is the active ingredient of 'CYMBALTA', which inhibits the uptake of both norepinephrine and serotonin. Duloxetine was first disclosed in U.S. Pat. No. 4,956,388 by Robertson, et al., and the synthesis of it was discussed in more detail by Deeter, et al., in Tetrahedron Letters, 31 (49), 7101 -04 ( 1990).

US 5,362,886 discloses a process for the preparation of Duloxetine, or an acid addition salt comprising

i. Condensing (S)~(-)-N, N-dimethyl-3 - (2-thienyl)-3-hydroxypropanamine with 1- fluoronaphthalene in presence of sodium hydride and potassium benzoate in DMSO so as to obtain (S)-(+)-N, N-dimethyl-3- (1-naphthalenyloxy) -3-(2- thienyl) propanamine (optionally converting it to its phosphate salt).

iii. If desired, converting Duloxetine to its acid addition salt as appropriate

Scheme- 1

PCT publication WO 2004/056795 discloses a process for the preparation of Duloxetine, or an acid addition salt thereof, which process comprises resolving racemic Duloxetine with a chiral acid so as to obtain a salt of the chiral acid and (+) Duloxetine, substantially free of (-) Duloxetine; and also disclosed a process for preparing (+) Duloxetine, or an acid addition salt thereof, comprise an O-alkylation intermediate process step which is carried out in the presence of a base and a phase transfer catalyst.

Scheme-2

EP 0457559 discloses a process for the preparation of D (+) Duloxetine oxalate as shown in the following scheme-3.

Scheme-3

In the prior art processes coupling of (S)-(+)-N,N-dimethyl-3-(2-thienyl)-3- hydroxypropanamine with 1-fluoronaphthalene is conducted in presence of a strong base, such as sodium hydride, in a protic polar solvent, such as DMSO, the dimesyl anion generated under the prior art reaction conditions, becomes a hazardous reaction due to non-compatibility of DMSO with strong bases(NaH, NaOH etc) and also caused partial or complete racemisatioή of the condensed product.

It has been a long standing need in industry to provide a process for the preparation of Duloxetine which overcomes the problems associated with prior art processes such as usage of sodium hydride in DMSO and the usage of expensive phase transfer catalysts the inventors have developed such a process, which is advantageous in obviating racemisation, so as to yield an enantiomerically pure form of Duloxetine. In particular, our process can be seen to achieve the above described advantage, by carrying out the coupling of (S)-(+)-N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fluoronaphthalene in presence of base which does not effect the chiral purity of the final product or coupling of N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fiuoronaphthalene in presence of base followed by resolution of the coupled product obtained in the reaction process (thereby obviating the opportunity for racemisation during preceeding intermediate process steps).

Summary of the Invention:

The present invention provides a process for preparation of Duloxetine, or an acid addition salt by coupling N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fluoro naphthalene in presence of an alkoxide in an organic polar solvent followed by resolution and demethylation yields Duloxetine or coupling (S)-(-)-N,N-dimethyl-3-(2- thienyl)-3 -hydroxy propanamine with 1-fiuoronaphthalene in presence of an alkoxide in an organic polar solvent followed by demethylation yields Duloxetine and also recycling the unwanted isomer in the preparation of Duloxetine.

Detailed description of the Invention:

In accordance with the present invention there is provided a process for the preparation of Duloxetine, or an acid addition salt comprising steps; i. Condensation of N, N-dimethyl-3~(2-thienyI)-3-hydroxypropanamine with 1- fluoro naphthalene so as to obtain N,N-dimethyl-3-(l-naphthalenyloxy) -3-(2- thienyl) propanamine (optionally converting it to its oxalate salt), ii. Resolving the racemic N,N-dimethyl-3-(l-naphthalenyloxy) -3-(2-thienyl) propanamine with a chiral acid so as to obtain a salt of the chiral acid and N 5 N- dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine iii. Demethylation of (S)-(+)-N,N-dimethyl-3-(l -naphthalenyloxy) -3-(2-thienyl) propanamine to get Duloxetine iv. If desired, converting Duloxetine to its acid addition salt as appropriate as shown in scheme-4

Condensation of N,N-dimethyI-3-(2-thienyl)-3-hydroxy propanamine with 1-fluoro naphthalene is carried out in presence of an alkoxide selected from potassium tert.butoxide, sodium methoxide and sodium ethoxide in an organic polar solvent selected from Dimethyl sulphoxide, N,N-Dimethyl formamide and N,N-Dimethyl acetamide at a temperature ranging from room temperature to 70°C, preferably at 50-60°C.

N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanami ne prepared according to the present invention as described above can be isolated as its acid addition salts which includes oxalate salt, phosphate salt, hydrochloride salt, nitrate salt and tartrate salt among which preferable one is the oxalate salt.

Resolution of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine is achieved with a suitable chiral acid in a suitable solvent. Preferably the chiral acids employed in a process according to the present invention are Tartaric acid, Mandelic acid, camphor sulphonic acid, Dibenzyl tartaric acid and Diparatolyl tartaric acid. Suitably, the solvents employed are alkanols, esters or a mixture of alkanol, ester and water.

(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine or its acid addition salt is converted to Duloxetine by demethylation in the presence of phenyl chloroformate, which is hydrolyzed to provide Duloxetine, or an acid addition salt thereof.

Pot . cere . Bucoxi.de Oxalic acid

D(-) Tartaric acid

Isopropyl alcohol Ethyl acecate Water

Duloxetine hydrochloride

Scheme-4

The present invention further relates to a process for the preparation of Duloxetine, or an acid addition salt comprising steps:

i. Condensing (S)-(-)-N, N-dimethyl-3 - (2-thienyl)-3-hydroxy propanamine with 1- fluoronaphthalene so as to obtain (S)-(+)-N, N-dimethyl-3 - (1-naphthalenyloxy)- 3-(2-thienyl) propanamine (optionally converting it to its oxalate salt).

ii. Demethylation of (S)-(+)-N, N-dimethyl-3 - ( 1 -naphthalenyloxy)-3 -(2-thienyl) propanamine to get Duloxetine.

iii. If desired, converting Duloxetine to its acid addition salt as appropriate.

Condensation of (S)-(-)-N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fluoronaphthalene is carried out in presence of an alkoxide in an organic polar solvent at a temperature ranging from room temperature to 70 0 C, preferably at 50-60 0 C.

(S) - (+) -N, N -dimethyl - 3 - (1 -naphthalenyloxy) - 3 - (2-thienyl)propanamine prepared according to the present invention as described above can be isolated as its acid addition salts which includes oxalate salt, phosphate salt, hydrochloride salt, nitrate salt and tartrate salt among which preferable one is the oxalate salt.

(S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine or its acid addition salt is converted to Duloxetine by demethylation in the presence of phenyl chloroformate, which is hydrolyzed to provide Duloxetine, or an acid addition salt thereof as shown in scheme-5.

Duloxetine hydrochloride Scheme-5

The present invention further relates to a process for the preparation of Duloxetine, or an acid addition salt comprising steps:

a. Racemization of the unwanted isomer of (-)-N,N-dimethyl-3-(l- naphthalenyloxy) -3-(2-thienyl) propanamine

b. Resolution of the racemic N,N-dimethyl-3-( 1-naphthalenyloxy) -3-(2-thienyl) propanamine and separating (S)-(+)-N, N-diraethyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine c. Demethylation of the (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2- thienyl) propanamine to get Duloxetine d. If desired, converting Duloxetine to its acid addition salt as appropriate.

Racemization of the (-)-N,N-dimethyl-3-( 1-naphthalenyloxy) -3-(2 -thienyl) propanamine is carried out in alkanols or polar aprotic solvents in presence of a base selected from alkali metal hydroxides preferably potassium hydroxide and alkoxide of alkali metals to get N,N-dimethyl-3-( 1-naphthalenyloxy) -3 -(2 -thienyl) propanamine.

Resolution of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine is achieved with a suitable chiral acid in a suitable solvent. Preferably the chiral acids employed in a process according to the present invention are Tartaric acid, Mandeiic acid, camphor sulphonic acid, Dibenzyl tartaric acid and Diparatolyl tartaric acid. Suitably, the solvents employed are alkanols, esters or a mixture of alkanol, ester and water.

(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2 -thienyl) propanamine or its acid addition salt is converted to (+) Duloxetine by demethylation in the presence of a reagent such as phenyl chloro formate, which is hydrolyzed to provide (+) Duloxetine, or an acid addition salt thereof.

The invention can be further illustrated by the below non-limiting examples.

Example-l:

N, N-dimethyI-3-(l-naphthalenyloxy) -3-(2-thienyl) propanamine oxalate

N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine (25.0gm) is dissolved in DMSO (150ml) at room temperature. Potassium.tertButoxide (15.5gm) is added over a period of 30min at room temperature. The reaction mixture is stirred for 30min at 25-30 C and 4- Fluoronaphthalene (24.45gm) is added slowly over a period of lhour. Reaction mass

temperature is slowly raised to 50-55 0 C and maintained for about όhours at that temperature. After the reaction is completed reaction mass is cooled to room temperature and Acetic acid (10ml) is slowly added over a period of lOmin and quenched in water at 20 0 C. Reaction mass pH is adjusted to about 5.0 with acetic acid and extracted with n-Hexane. Aq layer is separated and pH is adjusted to 11.5 with 5N NaOH and extracted with ethyl acetate. The ethyl acetate layer is washed and concentrated under vacuum. The residue is dissolved in ethyl acetate and treated with activated charcoal. To the clear filtrate Oxalic acid (15.3gm) is added. The reaction mixture is stirred for 2hrs and the precipitated Oxalate salt is filtered. Out put: 44.0gm (81.5 % yield)

Example-2:

(S) - (+)-N, N-dimethyl-3- (1-naphthalenyloxy) -3-(2-thienyl) propanamine tartrate hemihydrate;

N, N-dimethyl-3 -(1-naphthalenyloxy) -3-(2-thienyl) propanamine (20gm) is dissolved in ethyl acetate(120ml).Isopropyl alcohol(20ml) is charged to the reaction mass and the temperature is raised to around 40 0 C. To the reaction mixture D (-) tartaric acid (2.4gm dissolved in 6.0ml water) is added over a period of 45min.Reaction mass is maintained for 15 min at 40 0 C. Reaction mass is cooled to about 30 0 C and filtered the product. Washed with 40ml ethyl acetate and dried the product at 30-35 0 C under aerial drying. Out put: 6.4gm (yield: 22.0 %) Moisture content: 8.8% Specific optical rotation (C=I % methanol) : 74.24°

IRAnalysis: cm " ' 3323, 3053,2934,2970,1595,1397, 1264, 1236,1095,1067,795,775 and 705

IH NMR (300MHz, DMSO-d6) δ 6.88 (lH,d, Ar-H), 7.26-7.32(1 H,m, Ar-H), 7.42(lH,d, Ar-H), 7.78- 7.81(lH,m, Ar-H), 7.47-7.54(1 H,m, Ar-H), 7.47-7.54(1 H,m, Ar-H), 8.30-8.33(1 H,m, Ar-H), 5.83- 5.85(lH,dd, COCH),2.47-2.64(2H,m,CH 2 ), 3.03(2H,t,CH 2 N),2.47-2.64(6H,s, N(CH 3 ) 2 ), 3.13(2H,t,CH 2 ), 7.12(lH,d,Ar-H), 6.93-6.96(lH,dd,Ar-H),7.21-7.23(lH,dd, Ar-H),4.42(1H, tartrate)

13 C NMR (75MHz, DMSO-d6) δ 152.88,107.15,125.74,120.91, 134.58, 127.55, 125.34,126.35,121.89, 25.97,73.24,34.65,54.84,43.82,143.9425.12,126.78,125.0 and 177.9

ExampIe-3:

(+)-N-methyI-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (Duloxetine)

(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine tartrate salt (44.0gm) is suspended in Toluene (350ml) and DM water (350ml).Raised the temperature to 35-40 0 C and aq. ammonia (55ml) is added. Reaction mixture is stirred for 30min and the organic layer is separated and aq.layer is extracted with toluene. Combined the toluene layer, washed with water and concentrated under vacuum to get (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy) -3-(2-thienyl)propanamine base.

(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine is dissolved in toluene (140 ml) and the temperature is raised to 40°C.Diisopropylamine (1.76 gm) is added the temperature is raised to 50-55°C.Phenylchloroformate (21.4 gm) is added slowly over a period of 1.5 hours at 50-55 0 C. Reaction mass is maintained at 50-55 0 C for 1.5 hours. After the reaction is completed cool the reaction mass to 40 C and quenched the reaction mass in 1% NaHCO 3 (440ml). Organic layer is separated and washed with 0.5N HCl followed by 1% NaHCO 3 . Toluene is evaporated completely under vacuum and the obtained residue is dissolved in DMSO (480ml) and Caustic lye solution (16.7gm in 105ml water) is added over a period of one hour at 30-40 0 C. Reaction mass is stirred for 12 hrs at 40-45 0 C. After the reaction is completed cooled the reaction mass to 20 0 C and slowly quenched in DM water at 20 0 C. Reaction mass pH is adjusted to 5.7 with Acetic acid and washed the reaction mass with n-hexane. Aq.layer is separated and pH is adjusted to 10.5 with caustic lye. Extracted with ethyl acetate and ethyl acetate is concentrated under vacuum to get residue. The obtained residue is dissolved in ethyl acetate and treated with activated charcoal. The filtered ethyl acetate layer is concentrated to give Duloxetine (27gm. Yield; 95.0 %).

Duloxetine (27gm) is dissolved in ethyl acetate (90ml) and cooled the mass to 10 0 C. pH is adjusted to below 2.0 with IPA.HC1 over a period of one hour. Stirred the reaction mass for lhour at 10 0 C and lhour at O 0 C. Precipitated hydrochloride salt is filtered, washed with 100ml ethyl acetate and dried the product at 50-55 0 C. Out put: 14.0 gm.

Example-4: (+)-N-methyI-3-(l-naphthalenyloxy)-3-(2-thieπyl) propanamine (Duloxetine)

(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate salt (37.0gm) is suspended in Toluene (296ml) and DM water (296ml).Raised the temperature to 35-40 0 C and aq.ammonia (42ml) is added. Reaction mixture is stirred for 30min and the organic layer is separated and aq.layer is extracted with toluene. Combined the toluene layer, washed with water and concentrated under vacuum to get (S)-(+)-N, N-dimethyl-3-( 1 -naphthalenyloxy) -3-(2-thienyl)propanamine base.

(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine is dissolved in toluene (120ml) and the temperature is raised to 40 0 C. Diisopropylamine (1.5gm) is added the temperature is raised to 50-55 0 C. Phenylchloroformate (18.3gm) is added slowly over a period of 1.5 hours at 50-55 0 C. Reaction mass is maintained at 50-55 0 C for 1.5 hours. After the reaction is completed cool the reaction mass to 40 0 C and quenched the reaction mass in 1% NaHCθ 3 (370ml). Organic layer is separated and washed with 0.5N HCl followed by 1% NaHCO 3 Toluene is evaporated completely under vacuum and the obtained residue is dissolved in DMSO (370ml). Caustic lye solution (14.9gm in 83ml water) over a period of one hour at 30-40 0 C. Reaction mass is stirred for 12 hrs at 40-45 0 C.

After the reaction is completed cooled the reaction mass to 20 0 C and slowly quenched in DM water at 20°C.Reaction mass pH is adjusted to 7.7 with Acetic acid and washed the reaction mass with n-hexane. Aq.layer is separated and pH is adjusted to 10.5 with caustic lye. Extracted with ethyl acetate and ethyl acetate is concentrated under vacuum to get residue. The obtained residue is dissolved in ethyl acetate and treated with activated charcoal. The filtered ethyl acetate layer is concentrated to give Duloxetine. Out put: 26gm (Yield; 95.0 %)

Duloxetine (26gm) is dissolved in ethyl acetate (90ml) and cooled the mass to 10 0 C. pH is adjusted to below 2.0 with IPA.HC1 over a period of one hour. Stirred the reaction

mass for lhour at 10 0 C and lhour at O 0 C. Precipitated hydrochloride salt is filtered, washed with 100ml ethyl acetate and dried the product at 50-55 0 C. Out put: 13.8gm.

ExampIe-5:

Preparation of racemic Duloxetine:

D(-) Duloxetine(84 g) is dissolved in 1260ml of Methanol. To the reaction mass 35.5 g KOH powder is added and the temperature is raised to 70-75 0 C. Reaction mass is maintained for 2hrs at 70-75 0 C. Reaction mass is cooled to room temperature over a period of two hours. Reaction mass is quenched into DM water (1260ml) during 30-45 min. Reaction mixture is extracted with ethyl acetate and evaporated to give the title compound. Out put: 78.0 g SOR: 0.14 (1% MeOH)