The present complete specification claims priority from IN 3848/CHE/2012, filed on Sep 17, 2012 and IN 804/CHE/2013, filed on Feb 25, 2013.

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 a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration.Duloxetine is chemically known as (S)-(+)N-methyl-3(1-naphthalenyloxy)-3-(2-thienyl) propanamine and structurally represented as below:
Duloxetine is disclosed in US5023269 and marketed as Duloxetine hydrochloride under the brand name of CYMBALTA®. It is indicated for the treatment of major depressive disorder.

US 5362886 patent disclosed the duloxetine process, wherein (S)-(-)-N,N-dimethy1-3(2-thieny1)-3- hydroxypropanamine is reacted with 1-fluoronapthalene in presence of sodium hydride and potassium benzoate in dimethylsulfoxide (DMSO) to obtain (S)-(+)- N,N-dimethyl-3-(1-napthalenyloxy)-3-(2-thienyl)propanamine. The dealkylation of (S)-(+)-N,N-dimethyl-3-(1-napthalenyloxy)-3-(2-thienyl)propanamine yields duloxetine as a final product. The reaction steps as illustrated by the following scheme:

US 7538232 patent disclosed the process for the preparation of duloxetine, wherein (S)-3-methylamino-1-(2-thienyl)propan-1-ol is reacted with 1-fluoronapthalene in presence of potassium hydroxide in dimethylsulfoxide and toluene solvent system to obtain duloxetine. The reaction steps as illustrated by the following scheme:

US 7645890 patent exemplified a process for the preparation of duloxetine, wherein (S)-(-)-N,N-dimethy1-3(2-thieny1)-3- hydroxypropanamine is reacted with 1-fluoronapthalene in presence of a base and phase transfer catalyst in dimethylsulfoxide (DMSO) to obtain (S)-(+)- N,N-dimethyl-3-(1-napthalenyloxy)-3-(2-thienyl)propanamine. Dealkylation of (S)-(+)-N,N-dimethyl-3-(1-napthalenyloxy)-3-(2-thienyl)propanamine yields duloxetine. The reaction steps as illustrated by the following scheme:

The inventors of the present invention have developed an alternate process for the preparation of duloxetine hydrochloride, wherein (S)-3-methylamino-1-(2-thienyl)propan-1-ol is reacted with 1-fluoronapththaline in the presence of a base and optionally using phase transfer catalyst in a solvent mixture consisting of dimethylsulfoxide and ether.

SUMMARY OF THE INVENTION:

One aspect of the present invention is to provide a process for the preparation of duloxetine hydrochloride comprising the steps of:

a) reacting (S)-3-methylamino-1-(2-thienyl)propan-1-ol with 1-halonaphthalene in the presence of a base.solvent mixture consisting of dimethylsulfoxideand etheroptionally using phase transfer catalyst to obtain duloxetine, and

b) converting duloxetine into duloxetine hydrochloride salt.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of duloxetine, wherein (S)-3-methylamino-1-(2-thienyl) propan-1-ol is reacted with 1-halonaphthalene in the presence of base in a mixture of solventsto obtain duloxetine, and it is further converted into duloxetine hydrochloride.

One embodiment of the present invention is to provide a process for the preparation of duloxetine hydrochloridecomprising the steps of:

a) reacting (S)-3-methylamino-1-(2-thienyl)propan-1-ol with 1-halonaphthalene in the presence of a base, solvent mixture consisting of dimethylsulfoxideand ether optionally using phase transfer catalyst to obtain duloxetine, and

b) converting duloxetine into duloxetine hydrochloride salt.

According to the present invention (S)-3-methylamino-1-(2-thienyl) propan-1-ol is reacted with 1-halonaphthalene in the presence of a base and phase transfer catalyst in dimethylsulfoxideand ether solvent mixture at 30-60°C for 10-20hr to get reaction mixture. The resulting reaction mixture is dissolved in ethyl acetate and converted into duloxetine hydrochloride salt by adding isoproponolic hydrochloride.

According to the present invention 1-halonaphthalene is selected from 1-fluoro naphthalene, 1-chloronaphthalene, 1-bromonaphthalene, 1-iodonaphthalene, preferably 1-fluoro naphthalene.

According to the present invention the base used in the reaction is selected from potassium hydroxide, sodium hydroxide, potassium tertiary butoxide.

According to the present invention the phase transfer catalyst used in the reaction is selected from tetra butyl ammonium bromide, crown ethers, quaternary phosphonium salts.

According to the present invention the ether solvent used for the reaction is selected from methyl tertiary butyl ether, diethyl ether, tetrahydrofuran, methyl tertiary butyl ether, 2-methyl tetrahydrofuran, preferably methyl tertiary butyl ether.

According to the present invention, (S)-3-methylamino-1-(2-thienyl)propan-1-ol is prepared by the prior art process.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXPERIMENTAL SECTION:

Example-1: Preparation of duloxetine hydrochloride

To a stirred solution of Methyl tertiary butyl ether (MTBE) (225 ml) and Dimethyl sulfoxide (DMSO) (25ml), (S)-3-methyl amino-1-(2-thienyl)-1-propanol (25gm) was added. After getting the clear solution the Potassium hydroxide (40gm) was added at temperature 30-40°C. To this solution slowly added the 1-Fluoro naphthalene (24 gm) at 30-40°C. Raised the temperature to 50-60 CC and maintained it for 18-20 hours for completion of reaction. After completion of reaction, the reaction mass was slowly quenched in to chilled water (125 ml) at 10-15°C.The resulting solution pH was adjusted with aqueous HCI to 8.5-9.5 at temperature 10-15°C. Aqueous and organic layers were separated at 30-40°C. Aqueous layer was extracted with of MTBE (100 ml). Combined organic layers were washed with purified water (100ml) finally washed with sodium chloride solution. The resulted organic layer was distilled under reduced pressure to get Duloxetine. The crude was dissolved in Ethyl acetate (225 ml) and treated with IPA HCI by adjusting the pH to 3.5-5.0. the separated solid was filtered and washed with Ethyl acetate (10 ml), dried to get 30gm of pure Duloxetine Hydrochloride.

Example-2: Preparation of duloxetine hydrochloride

To a stirred solution of 2-Methyl tetra hydro furan (225 ml) and Dimethyl sulfoxide (DMSO) (25 ml), (S)-3-methyl amino-1-(2-thienyl)-1-propanol (25gm) was added. After getting the clear solution the Potassium hydroxide (40gm) was added at temperature 30-40°C. To this solution slowly added 1-Fluoro naphthalene (24gm) at 30-40°C. Raised the temperature to 70-75 °C and maintained it for 20-22 hours for completion of reaction. After completion of the reaction, slowly quenched the reaction mass in to chilled water (125 ml) at 10-15°C.Adjusted the pH of reaction mass with aqueous HCI to 8.5-9.5 at temperature10-15°C. Aqueous and organic layers were separated at 30-40°C. Aqueous layer was extracted with 2-Methyl tetra hydro furan (100 ml). Combined organic layers were washed with purified water (100ml) finally washed with sodium chloride solution. The resulted organic layer was distilled under reduced pressure and the traces of 2-Methyl tetra hydro furan were removed by ethyl acetate stripping, the crude Duloxetine obtained. The crude was dissolved in Ethyl acetate (225ml) and treated with IPA HCI by adjusting the pH to 3.5-5.0. After completion of charcoal treatment, the mass was filtered and washed with Ethyl acetate (10 ml), wet material was dried to get 30gm of pure Duloxetine Hydrochloride.

Example-3: Preparation of duloxetine hydrochloride

To a stirred solution of methyl tertiary butyl ether (900ml) and dimethyl sulfoxide (100ml), (S)-3-methyl amino-1-(2-thienyl)-1-propanol (100gm) was added at 25-35°C and stirred at same temperature for 10-20 min to obtain the clear solution. Potassium hydroxide powder (165gm) followed by tetra butyl ammonium bromide (TBAB) (8gm) was added at 25-35°C to the resulting reaction mass and stirred at same temperature for 25-35min.1-fluoronaphthalene (95gm) was added to the reaction mass at 25-35cC over a period of 45-90 min, slowly raised the temperature to 50-60°C over a period of 3-4 hrs and maintained at same temperature for 21-24 hrs. after completion of the reaction, the mass was cooled to 15-25°C, slowly added water (500ml) at same temperature over a period of 30-45 min and stirred for 25-35 min upon raising the solution temperature to 30-40°C. The whole mass was allowed to settle for 30 min and separated the resulting aqueous and organic layer.

The organic layer was distilled off completely to get residue. The resulting residue was dissolved in Ethyl acetate (900ml) at 25-35°C and subjected to carbon treatment at same temperature upon stirring for 25-35min. Reaction mass was filtered over hyflow bed to separate the carbon , washed the bed with Ethyl acetate (100ml). Both the filtrates are combined each other and taken into another RB flask to proceed for hydrochloride salt formation. The RB flask containing Ethyl acetate filtrate was cooled to 10-20°C, slowly adjusted pH of the solution to 3.5- 4 using IPA. HCI, and stirred at same temperature for 3-4 hrs. The resulting heterogeneous mass was cooled to 0-5°C, and stirred at same temperature for 1-2 hrs. The solid obtained was filtered, washed the wet solid with Ethyl acetate (chilled) and suck dried for 30 min. The resulting wet compound was suspended in Ethyl acetate (750ml), heated to 50-60°C and stirred at same temperature for 25-35min. Reaction mass was cooled to 25-35°C and stirred at same temperature for 3-4 hrs. The solid obtained was filtered, washed with Ethyl acetate (100ml) and suck dried for 30 min. The wet solid obtained was unloaded and dried at 50-55°C for 8-10hrs under vacuum to obtain 140gm of dry solid of final API of Duloxetine Hydrochloride (HPLC purity 99.9 %).

Example-4: Preparation of duloxetine hydrochloride

To a stirred solution of methyl tertiary butyl ether (900ml) and dimethyl sulfoxide (100ml), (S)-3-methyl amino-1-(2-thienyl)-1-propanol (100gm) was added at 25-35°C and stirred at same temperature for 10-20 min to obtain the clear solution. Potassium hydroxide powder (165gm) followed by tetra butyl ammonium bromide (TBAB) (8gm) was added at 25-35°C to the resulting reaction mass and stirred at same temperature for 25-35min.1-fluoronaphthalene (95gm) was added to the reaction mass at 25-35°C over a period of 45-90 min, slowly raised the temperature to 50-60°C over a period of 3-4 hrs and maintained at same temperature for 21-24 hrs. after completion of the reaction, the mass was cooled to 15-25°C, slowly added water (500ml) at same temperature over a period of 30-45 min and stirred for 25-35 min upon raising the solution temperature to 30-40°C. The whole mass was allowed to settle for 30 min and separated the resulting aqueous and organic layer.

The organic layer was distilled off completely to get residue. The resulting residue was dissolved in Ethyl acetate (900ml) at 25-35°C and subjected to carbon treatment at same temperature upon stirring for 25-35min. Reaction mass was filtered over hyflow bed to separate the carbon , washed the bed with Ethyl acetate (100ml). Both the filtrates are combined each other and taken into another RB flask to proceed for hydrochloride salt formation. The RB flask containing Ethyl acetate filtrate was cooled to 10-20°C, slowly adjusted pH of the solution to 3.5- 4 using IPA. HCI, and stirred at same temperature for 3-4 hrs. The resulting heterogeneous mass was cooled to 0-5°C, and stirred at same temperature for 1-2 hrs. The solid obtained was filtered, washed the wet solid with Ethyl acetate (chilled) and suck dried for 30 min. The resulting wet compound was suspended in Ethyl acetate (750ml) and IPA (750ml) mixture, heated to 50-60°C and stirred at same temperature for 25-35min. Reaction mass was cooled to 25-35°C and stirred at same temperature for 3-4 hrs. The solid obtained was filtered, washed with Ethyl acetate (100ml) and suck dried for 30 min. The wet solid obtained was unloaded and dried at 50-55°C for 8-10 hrs under vacuum to obtain 140gm of dry solid of final API of Duloxetine Hydrochloride (HPLC purity 99.9 %).

WE CLAIM:

1. A process for the preparation of duloxetine hydrochloride comprising the steps of:

a) reacting (S)-3-methylamino-1-(2-thienyl)propan-1-ol with 1-halonaphthalene in the presence of a base, solvent mixture consisting of dimethylsulfoxide and ether optionally using phase transfer catalyst to obtain duloxetine, and

b) converting duloxetine into duloxetine hydrochloride salt.

2. The process according to claim 1, wherein 1-halonaphthalene is selected from 1-fluoro naphthalene, 1-chloronaphthalene, 1-bromonaphthalene, 1-iodonaphthalene.

3. The process according to claim 1, wherein base is selected from potassium hydroxide, sodium hydroxide, potassium tertiary butoxide.

4. The process according to claim 1, wherein phase transfer catalystis selected from tetra butyl ammonium bromide, crown ethers, quaternary phosphonium salts.

5. The process according to claim 1, whereinether solvent is selected from methyl tertiary butyl ether, tetrahydrofuran, methyl tertiary butyl ether, 2-methyl tetrahydrofuran.