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

BACKGROUND OF THE INVENTION:
Duloxetine hydrochloride is chemically known as (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine hydrochloride, the structure of formula (1).

Duloxetine is 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 U.S. patent No. 7,538,232 describes preparation of duloxetine by arylation of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene 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 with 1-fluoronaphathalene in the presence of potassium tert-butoxide as base and dimethyl sulfoxide as solvent. Duloxetine obtained by this process requires further purification to get chiral pure duloxetine.
Present invention has developed an improved industrial viable process for the preparation of duloxetine hydrochloride, involves fewer reaction steps at room temperature, lesser reaction time, easy work-up and provides higher yields of product with high purity and opts with very low levels of impurities.

SUMMARY OF THE INVENTION:

The present invention relates to an improved process for the preparation of duloxetine hydrochloride comprising;
a) reacting (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene in presence of potassium hydroxide having particle size 250 to 600 microns and dimethyl sulfoxide,
b) Optionally isolating duloxetine and converting to pure duloxetine hydrochloride.

The present invention also provides a process for the preparation of duloxetine hydrochloride having R-isomer less than 0.5 %.

DETAILED DESCRIPTION OF THE INVENTION:

One aspect of the present invention provides an improved process for the preparation of duloxetine hydrochloride by arylation of (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene in presence of potassium hydroxide having particle size 250 to 600 microns and dimethyl sulfoxide, optionally isolating duloxetine and converting to pure duloxetine hydrochloride.

Yet another aspect of the present invention provides a process for the preparation of pure duloxetine hydrochloride comprising;
a) reacting (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene in presence of potassium hydroxide having particle size 250 to 600 microns and dimethyl sulfoxide,
b) Optionally isolating duloxetine and converting to duloxetine hydrochloride.
c) Optionally purifying duloxetine hydrochloride.

Another aspect of the present invention provides a process for the preparation of duloxetine hydrochloride having 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 potassium hydroxide having particle size 250 to 600 microns and dimethyl sulfoxide,
b) Optionally isolating duloxetine and converting to duloxetine hydrochloride.
c) Optionally purifying duloxetine hydrochloride.

According to the present invention, wherein (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol can be obtained by the process known in the art such as US 5023269 and US 5362886.

According to the present invention, wherein reacting (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene in presence of potassium hydroxide having particle size 250 to 600 microns.

According to the present invention, wherein Particle size and distribution of the particle size of the solid potassium hydroxide is dependent upon the permeability of the stratified formation. The particle size can be within the range of about 250 to about 600 microns is obtain by milling through Tyler Screen mesh size is preferably about 10 to about 100 mesh. Preferably from about 20 to 80, more preferably from about 25 to 70, most preferably from about 30 to 45, the particle size of the 345 microns of potassium hydroxide obtained by milling through Tyler screen 45 mesh.

According to the present invention, wherein reaction is carried at a temperature 15-35°C, preferably from about 20 to 30°C.

According to the present invention, duloxetine free base is converting into duloxetine hydrochloride and further optionally purifying duloxetine hydrochloride can be obtained by the process known in the art such as US8269023 B2, IN268490, IN 3314/KOLNP/2009A, IN 1474/MUM/2014A and IN 0303/MUM/2015.

The process of the present invention has following advantages:
i. Cost effective,
ii. Lesser reaction time and lesser purification steps
iii. Provides higher yields of product with high purity,
iv. Reaction is involved at room temperature,
v. Industrial viable process.

According to the present invention, Duloxetine hydrochloride is characterized by obtained by the process of the present invention is having a purity of greater than about 95%, or greater than about 98%, or greater than about 99%, when measured by using high performance liquid chromatography (HPLC) and the details are given below;
Instrument : HPLC equipped with Pump, UV detector and Recorder.
Column : Zorbax SB-C18 (4.6 x 250mm), 5µm.
Wavelength : UV Detector 240nm
Flow rate : 1.5mL/min
Injection volume : 20?L.
Auto sampler temperature: 10°C
Column oven temperature: 50°C.
According to the present invention, Duloxetine hydrochloride is characterized by obtained by the process of the present invention is having a chiral purity of greater than about 98%, or greater than about 99%, or greater than about 99.8%, when measured by using Chiral high performance liquid chromatography (HPLC) and the details are given below;
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.

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.

Examples:
Example-1: Process for the preparation of Pure Duloxetine HCl

(S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (25 g,) was dissolved in dimethyl sulfoxide (75 mL). Potassium hydroxide (48 g, particle size 354 microns) was added and the resulting mixture was stirred for 40 minutes at 25-30°C. To this solution, 1-fluoronaphathalene (22 g) was charged dropwise within 25-30 min at 25-30°C. The reaction mixture was stirred at 20-30 °C for 8 hours. The reaction mixture was allowed to cool to 12 °C and poured into cold water (200 mL). Added cyclohexane (125 mL). Separate both the layers. The organic layer was concentrated under reduced pressure and obtained compound was dissolved in ethyl acetate (175 mL). Ethyl acetate HCl (48 g) was added at 15-30°C, stirred reaction mass at 20-25 °C for 1h. The solid was filtered, washed with ethyl acetate and dried at 45 °C under reduced pressure. Thus obtained pure duloxetine hydrochloride.
Yield: 41g g. HPLC purity: 99.9%; Chiral purity: 99.80 %; R-isomer = 0.20 %

Example-2
Process for the preparation of Duloxetine HCl
(S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (25 g,) was dissolved in dimethyl sulfoxide (75 mL). Potassium hydroxide (48 g, particle size 250 microns) was added and the resulting mixture was stirred for 40 minutes at 25-30°C. To this solution, 1-fluoronaphathalene (22 g) was charged dropwise within 25-30 min at 25-30°C. The reaction mixture was stirred at 20-30 °C for 8 hours. The reaction mixture was allowed to cool to 12 °C and poured into cold water (200 mL). Added cyclohexane (125 mL). Separate both the layers. The organic layer was concentrated under reduced pressure and obtained compound was dissolved in ethyl acetate (375 mL). Ethyl acetate HCl (40 g) was added at 15-30°C, stirred reaction mass at 20-25 °C for 1h. The solid was filtered, washed with ethyl acetate and dried at 45 °C under reduced pressure. Thus obtained pure duloxetine hydrochloride.
Yield: 40.4 g. HPLC purity: 99.8%; Chiral purity: 99.84 %; R-isomer = 0.16 %.

Example-3
Process for the preparation of Duloxetine HCl
(S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (25 g,) was dissolved in dimethyl sulfoxide (75 mL). Potassium hydroxide (48 g, particle size 595 microns) was added and the resulting mixture was stirred for 40 minutes at 25-30°C. To this solution, 1-fluoronaphathalene (22 g) was charged dropwise within 25-30 min at 25-30°C. The reaction mixture was stirred at 20-30 °C for 8 hours. The reaction mixture was allowed to cool to 12 °C and poured into cold water (200 mL). Added cyclohexane (125 mL). Separate both the layers. The organic layer was concentrated under reduced pressure and obtained compound was dissolved in ethyl acetate (375 mL). Ethyl acetate HCl (48 g) was added at 15-30°C, stirred reaction mass at 20-25 °C for 1h. The solid was filtered, washed with ethyl acetate and dried at 45 °C under reduced pressure. Thus obtained pure duloxetine hydrochloride.
Yield: 36.7g. Chiral purity: 99.89 %; R-isomer = 0.11 %.

Comparative example: Preparation of Duloxetine HCl
(S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (10 g, 0.0584 mol) was dissolved in dimethyl sulfoxide (30 mL). Potassium hydroxide (16.74 g, particle size 850 microns) 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:1) A process for the preparation of duloxetine hydrochloride comprising:
a) reacting (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene in presence of potassium hydroxide having particle size 250 to 600 microns and dimethyl sulfoxide,
b) optionally isolating duloxetine and converting to duloxetine hydrochloride

2) The process according to claim 1, wherein potassium hydroxide having particle size 300 to 500 microns

3) The process as claimed in claim 1, wherein step (a) is carried out by heating in the
range of 25-40 °C.

4) The process for preparation of duloxetine as claimed in claim 1, wherein duloxetine
containing R-isomer less than 0.5 %

5) The process for preparation of duloxetine hydrochloride as claimed in claim 1, duloxetine hydrochloride having a purity more than 99.9% by HPLC.

6) The process for preparation of duloxetine hydrochloride as claimed in claim 1, duloxetine hydrochloride having chiral purity more than 99.8%.

7) The process for preparation of duloxetine hydrochloride as claimed in claim 1, wherein duloxetine hydrochloride containing R-isomer less than 0.3 %.

8) A process for the preparation of duloxetine hydrochloride containing R-isomer less than 0.3 % comprising:
a) reacting (S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol with 1-fluoronaphathalene in presence of potassium hydroxide having particle size 250 to 600 microns and dimethyl sulfoxide at a temperature 25-40°C,
b) optionally isolating duloxetine and converting to pure duloxetine hydrochloride.

9) The process for preparation of duloxetine hydrochloride as claimed in claim 8, duloxetine hydrochloride having a purity more than 99.95% by HPLC.