DESC:FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of duloxetine.

BACKGROUND OF THE INVENTION:
The chemical name of duloxetine hydrochloride is (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine hydrochloride (1).

Duloxetine was disclosed in U.S. patent No. 4,956,388 and its acid addition salts in U.S.patent No. 5,362,886. Duloxetine is a serotonin and norepinephrine re-uptake dual inhibitor and a highly efficient antidepressant agent for treating psychiatric disorders. It is marketed under the brand name Cymbalta® in USA.

The publication Tetrahedron Asymmetry 2005, 16, 1873 and PCT application WO 2013056809 describes preparation of duloxetine by arylation of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (2) with 1-fluoronaphathalene (3) in the presence of sodium hydride as base and dimethyl sulfoxide as solvent. Sodium hydride is very hazardous reagent because it is pyrophoric and reacts violently with water with evolution of hydrogen gas.

The U.S. patent No. 7,538,232 describes preparation of duloxetine by arylation of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (2) with 1-fluoronaphathalene (3) in the presence of potassium hydroxide as base and dimethyl sulfoxide as solvent. This arylation reaction results into the complete racemization to give 1:1 mixture of duloxetine and (R)-(-)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (i.e. R-isomer). The racemization was minimized to obtain duloxetine containing R isomer upto 1% by using mixture of dimethyl sulfoxide and toluene as solvent. However, the use of mixed organic solvents has disadvantageous in view of environmental protection and high cost due to solvent recovery.

The U.S. patent No. 8,530,674 describes preparation of duloxetine containing R-isomer upto 2.5% by arylation of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (2) with 1-fluoronaphathalene (3) in the presence of potassium tert-butoxide as base and dimethyl sulfoxide as solvent. Duloxetine obtained by this process requires further purification to get chirally pure duloxetine.

The prior art methods have disadvantages such as:
i. racemization,
ii. higher cost,
iii. hazardous reagents,
iv. non- environment friendly etc.

Therefore, there is still a need to provide a process for preparing chirally pure duloxetine.

SUMMARY OF THE INVENTION:
The present invention relates to a process for the preparation of duloxetine containing R-isomer less than 0.5 % comprising
a) reacting compound (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene in presence of sodium amide and dimethyl sulfoxide,
b) isolating duloxetine and
c) optionally, converting duloxetine to duloxetine salt.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a process for the preparation of duloxetine containing R-isomer less than 0.5 % by arylation of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene in presence of sodium amide and dimethyl sulfoxide.

The present invention relates to a process for the preparation of duloxetine containing R-isomer less than 0.4 % by arylation of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene in presence of sodium amide and dimethyl sulfoxide.

The present invention relates to a process for the preparation of duloxetine containing R-isomer less than 0.35 % by arylation of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene in presence of sodium amide and dimethyl sulfoxide.

The quantity of sodium amide is 1 to 2 mol equivalent, preferably, 1.1 to 1.4 mol equivalent of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol.

The quantity of dimethyl sulfoxide is 1 to 5 times, preferably 2 to 3 times of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol.

The arylation is carried out by heating at a temperature in the range of 60-100 °C, preferably at a temperature in the range of 80-90 °C.

The isolation of duloxetine is carried out by extracting the reaction mixture in a suitable organic solvent and concentrating the organic layer under reduced pressure. The suitable organic solvent includes cyclohexane, toluene, C3-8 esters, C2-8 ethers, dichloromethane.

The process of the present invention further comprises preparation of duloxetine salt by reacting duloxetine with organic or inorganic acid in a suitable solvent. The organic acid includes oxalic, maleic, para-toluenesulfonic, methanesulfonic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid. The inorganic acid includes hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid. Suitable solvent includes C3-8 ketones, C3-8 esters, C2-8 ethers, C1-8 alcohols, and mixtures thereof.

The process of the present invention has following advantages:
i. racemization less than 0.5 %,
ii. cost effective,
iii. no hazardous reagents and
iv. environment friendly.

The present invention is described in the following example, however it should be noted that the scope of present invention is not limited by the example.

EXPERIMENTAL:
Conditions for Chiral HPLC:
Column: Chiralcel OJ-H (4.6 x 250mm), 5µm,
Column oven temperature: 40° C;
Solvent: n-Hexane: ethanol: diethylamine: glacial acetic acid (970:30:01:0.5),
Flow rate: 1 mL/minute;
Wavelength: UV 230 nm.

Example:
Preparation of duloxetine HCl using sodium amide
(S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (100 g, 0.584 mol) was dissolved in dimethyl sulfoxide (200 mL). Sodium amide (29.6 g, 0.759 mol) was added and the resulting mixture was stirred for 30 minutes. To this solution, 1-fluoronaphathalene (85.2 g, 0.584 mol) was charged dropwise within 30 min at 80-87 °C. The reaction mixture was stirred at 85-87 °C for 9 hours. The reaction mixture was allowed to cool to 30 °C and poured into cold water (1600 mL). The pH of aqueous solution was adjusted to 5 with acetic acid then washed with cyclohexane. The pH of aqueous solution adjusted to 13.5 with 5N sodium hydroxide solution. This aqueous solution was extracted with cyclohexane (1 X 600mL; 2 X 300 mL) and the organic layer was washed with brine solution. The organic layer was concentrated under reduced pressure and the oily residue was dissolved in ethyl acetate (1500 mL). Ethyl acetate HCl (221.8 g; 8.9%) was added at 0-6 °C and the stirring was continued at 20-25 °C for 1h. The solid was filtered, washed with ethyl acetate and dried at 45 °C for 13 hours under reduced pressure. Yield: 139 g. HPLC purity: 99.81%; Chiral purity: 99.66%; R-isomer = 0.34%.

Comparative example:
Preparation of duloxetine HCl using potassium hydroxide
(S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (10 g, 0.0584 mol) was dissolved in dimethyl sulfoxide (30 mL). Potassium hydroxide powder (16.74 g, 0.254 mol) was added at 20-24°C and the resulting mixture was stirred for 30 minutes. To this solution, 1-fluoronaphathalene (8.52 g, 0.0584 mol) was charged. The reaction mixture was stirred at 83
°C for 9 hours. The reaction mixture was allowed to cool to 30 °C and poured into cold water (240 mL). The pH of aqueous solution was adjusted to 5 with acetic acid and washed with cyclohexane. The pH of aqueous solution adjusted to 13.5 with 5N sodium hydroxide solution. This aqueous solution was extracted with cyclohexane (1 X 60 mL; 2 X 30 mL) and the organic layer was washed with brine solution. The organic layer was concentrated under reduced pressure and the oily residue was dissolved in ethyl acetate (150 mL). Ethyl acetate HCl (19.2 g; 8.9%) was added at 5-8 °C and the stirring was continued at 25 °C for 1.5 h. The solid was filtered, washed with ethyl acetate and dried 45°C for 20 hours under reduced pressure. Yield: 13 g. HPLC purity: 99.92%; Chiral purity: 81.85%; R-isomer = 18.15%.
,CLAIMS:Claim 1. A process for the preparation of duloxetine containing R-isomer less than 0.5 %
comprising
a) reacting (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene in presence of sodium amide and dimethyl sulfoxide,
b) isolating duloxetine and
c) optionally, converting duloxetine to duloxetine salt.

Claim 2. The process as claimed in claim 1 wherein the quantity of sodium amide is 1 to 2
mol equivalent of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol.

Claim 3. The process as claimed in claim 2 wherein the quantity of sodium amide is 1.1 to
1.4 mol equivalent of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol.

Claim 4. The process as claimed in claim 1 wherein the quantity of dimethyl sulfoxide is 1 to
5 times of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol.

Claim 5. The process as claimed in claim 4 wherein the quantity of dimethyl sulfoxide is 2 to
3 times of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol.

Claim 6. The process as claimed in claim 1 wherein step (a) is carried out by heating in the
range of 60-100 °C.

Claim 7. The process as claimed in claim 6 wherein step (a) is carried out by heating in the
range of 80-90 °C.

Claim 8. The process for preparation of duloxetine as claimed in claim 1 wherein duloxetine
containing R-isomer less than 0.4 %.

Claim 9. The process for preparation of duloxetine as claimed in claim 1 wherein duloxetine
containing R-isomer less than 0.35 %.

Claim 10. The process as claimed in claim 1 wherein duloxetine salt in step (c) is duloxetine
hydrochloride.