“PROCESS FOR THE PREPARATION OF (S)-DAPOXETINE”
FIELD OF THE INVENTION:
The present invention relates to improved process for the preparation of (S)-Dapoxetine or an acid addition salt thereof and also provides a enantiomerically pure form of Dapoxetine hydrochloride
Background of the invention:
Dapoxetine hydrochloride is available under the brand name PRILIGY™ in Europe. Dapoxetine hydrochloride is chemically known as S(+)-N,N-dimethyl-2-[l-(naphtha leneeyloxy)-ethyl]benzene methanamine hydrochloride (here after referred by its generic name dapoxetine) and represented by the formula (I).
US 5,135,947 describes l-phenyl-3-napthalenyloxypropanamines including Dapoxetine or pharmaceutically acceptable acid addition salts thereof, a pharmaceutical composition and a method of treatment.
The US '947 patent discloses a process for the preparation of dapoxetine and its salts which is illustrated by scheme below:

The reported process for the preparation of compound of formula (l) by condensation of 3-(N,N-dimethylamino)-3-phenyl-1-propanol with 1-fluoronaphthalene uses sodium hydride which is hazardous and difficult to handle on industrial scale. Whereas the process of present invention uses mild and simple base sodium hydroxide which is cheaper and easy to handle on commercial scale.
US 5, 292,962 discloses a process for the preparation of Dapoxetine and its salts which is illustrated by scheme below:

(S)-3-chloro-1-phenyl-1-propanol reacted with naphthalene-1-ol in presence of base to give 3-(naphthalene-1-yloxy)-1-phenyl propan-1-ol. Further it is reacted with methane sulfonyl chloride in presence of a catalyst; followed by addition dimethyl amine to give crude Dapoxetine. The crude Dapoxetine is further purified in presence of ethyl acetate and HCl to give a Dapoxetine hydrochloride.
The processes reported in the prior art are expensive; difficult to handle on commercial scale, requires additional purification steps intermittently thus ending up with low yields and purities of the final product thus rendering the process not viable on commercial scale. Hence there is a need in the art for an improved process for the preparation of dapoxetine and its intermediates, which avoids the use of potentially hazardous chemicals, the likely formation of isomeric and other process related impurities, while enhancing the desired product Dapoxetine or a pharmaceutically acceptable salt resulting in higher yield and purity.
According to the above prior art processes which involves the condensation reaction of compound of formula (XI) with methanesulphonyl chloride in presence of catalyst causes low yield and high impurity profile.
Hence, the use of catalyst may not feasible and it is not economical for industrial scale for the preparation of Dapoxetine hydrochloride (I).
In view of the foregoing, the present inventors have result of extensive studies, the efficiency is extremely only the condensation reaction of compound of formula (XI) with methanesulphonyl chloride is carried out in absence of catalyst, it was found that the corresponding (1S)-3-(naphthalene-1-yloxy)-1-phenylpropyl methanesulfonate (XII) can be produced in high yield and purity with advantages of low consumption of solvents.
SUMMARY OF THE INVENTION
One aspect of the present invention is to provide an improved process for the preparation of Dapoxetine hydrochloride of formula (I) comprising the steps of;

a) Condensing (S)-3-chloro-1-phenyl propanol of formula (IX) with naphthalen-1-ol (X) in presence of a base to give compound of formula (XI),
b) reacting the compound of formula (XI) with methanesulphonyl chloride in absence of catalyst to produce compound of formula (XII),
c) further the product of step b) is reacting with aqueous dimethyl amine solution in presence of a base to give a compound of formula (XIII), and
d) the isolating Dapoxetine hydrochloride of formula (I).
The above synthetic process is illustrated as per the following Scheme-III.
In yet another aspect of the present invention is to provide an enantiomerically pure form of Dapoxetine hydrochloride of formula (I).
Detailed Description of the Invention
The present invention relates to an improved process for the preparation of Dapoxetine or an acid addition salt thereof and also provides a enantiomerically pure form of Dapoxetine hydrochloride
One embodiment of the present invention provides an improved process for the preparation of Dapoxetine hydrochloride of formula (I) comprising the steps of;

a) Condensing (S)-3-chloro-1-phenyl propanol of formula (IX) with naphthalen-1-ol (X) in presence of a base to give compound of formula (XI),
b) reacting the compound of formula (XI) with methanesulphonyl chloride in absence of catalyst to produce compound of formula (XII),
c) further the product of step b) is reacting with aqueous dimethyl amine
solution in presence of a base to give a compound of formula (XIII), and
d) the isolating Dapoxetine hydrochloride of formula (I).
According to the present invention, the (S)-3-chloro-1-phenyl propanol is reacted with naphthalen-1-ol in presence of a base to give compound of formula (XI); further it is reacted with methane sulphonyl chloride (or) para toluene sulfonyl chloride in absence of a catalyst at a suitable solvent to give a compound of formula (XII). The aqueous dimethyl amine solution is treated with compound of formula (XII) in presence of a base to give crude Dapoxetine (XIII); further it was purified in presence of mineral acid and a solvent to give a Dapoxetine hydrochlorideof formula (I).
According to the present invention, the base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.
According to the present invention, the solvent is selected from ethyl acetate, tetrahydrofuran, isopropyl acetate, isopropyl ether, toluene, methanol, ethanol or isopropyl alcohol
According to the present invention, the compound of formula (I) or Dapoxetine hydrochloride having HPLC purity is not less than 99.5%.
Another embodiment of the present invention is to provide an enantiomerically pure form of Dapoxetine hydrochloride of formula (I).
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Experimental procedure:
Example-1: Preparation of (S)-Dapoxetine hydrochloride.
a) Preparation of (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol
To the clean and dry RB flask charged toluene (700 ml), naphthalen-1-ol (85 g, 0.589 moles) and sodium hydroxide (25 g, 0.625 moles) and the mixture was heated to reflux at 100-115°C and collected water by azeotropic distillation for 2-3 hrs. The reaction mixture was cooled to 25-30°C, slowly added the mixture of (S)-3-chloro-1-phenyl propan-1-ol (100 g, 0.586 moles) and dimethylsulphoxide (100 ml) at same temperature. The reaction mixture was raised to reflux and maintain for 2-3 hrs, (checked TLC for completion of reaction). Followed by addition of water (400 ml) and stirred the reaction mixture to separated layers. The toluene layer was washed twice with 10% sodium hydroxide solution (150 ml) and it was concentrated (50%) under reduced pressure to obtained (S)-3-(naphthalen-1-yloxy)-1-phenyl propan-1-ol.
b) Preparation of (S)-3-(naphthalen-1-yloxy)-1-phenylpropyl methane
sulfonate
To the clean and dry RB flask and charged toluene (500 ml ), (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol (100 g, 0.359 moles) and cooled the mixture to 0-5°C, followed by addition of triethyl amine (85 gm, 0.841moles) and methane sulphonyl chloride (75 g, 0.654 moles); The resulting reaction mixture was stirred for 1-2 hrs at 0-5°C for completion of the reaction, water (1000 ml) was added the reaction mixture to separated layers. The resultant toluene layer was washed with purified water (200 ml) to get a desired product.
c) Preparation of (1S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenyl
propan-1-amine hydrochloride
A solution of (S)-3-(naphthalen-1-yloxy)-1-phenylpropyl methanesulfonate in toluene was added to 40% dimethyl amine solution (356 g, 7.9 moles) and stirred at ambient temperature for 20-24 hrs. After completion of reaction (checked by TLC).

The aqueous layer containing dimethyl amine was separated and the desired toluene layer was washed twice with water (2 x 200 ml) and charged purified water (500 ml) and adjusted pH to 1-2 with dilute hydrochloride, stirred the mixture to separated layers. Finally the toluene layer was distilled out completely to get N, N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine hydrochloride (or) crude Dapoxetine HCl.
The crude Dapoxetine hydrochloride was recrystallized in presence of isopropyl alcohol (250 ml) to obtain pure titled compound 65.0 gm .
Example-2: Preparation of (S)-Dapoxetine hydrochloride
a) Preparation of (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol
To the clean and dry RB flask charged toluene (700 ml), naphthalen-1-ol (85 g, 0.589 moles) and sodium hydroxide (25 g, 0.625 moles) and mixture heated to reflux at 100-115°C and collected water by azeotropic distillation for 2-3 hrs. The reaction mixture was cooled to 25-30°C, followed by addition of (S)-3-chloro-1-phenyl propan-1-ol (100 g, 0.586 moles) and dimethylsulphoxide (100 ml) at same temperature. The reaction mixture was raised to reflux and maintain for 2-3 hrs. (Check TLC for completion of reaction). After completion of reaction, water (400 ml) was added and stirred the reaction mixture to separated layers. Toluene layer was washed twice with 10% sodium hydroxide solution (150 ml) followed by brine wash. The resultant toluene layer was concentrated (50%) under reduced pressure to obtained (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol.
b) Preparation of (S)-3-(naphthalen-1-yloxy)-1-phenylpropyl methane
sulfonate
To the clean and dry RB flask and charged MDC (500 ml), (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol (100 g, 0.34 moles) and cooled to mixture to 0-5°C. Added diisopropylethyl amine (85 g, 0.841 moles) to the reaction mixture at 0-5°C followed by addition of methane sulphonyl chloride (75 g, 0.654 moles). The reaction mixture was stirred for 1-2 hrs at 0-5°C, after completion of reaction, water (1000 ml) was added and stirred to separate layers. The resultant aqueous layer was extracted with dichloromethane (300 ml). Total dichloromethane layer was washed with purified water (200 ml) to get a solution of title compound.

c) Preparation of (S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenyl propan-1-amine hydrochloride
A solution of (S)-3-(naphthalen-1-yloxy)-1-phenylpropyl methanesulfonate in dichloromethane was added to 40% dimethyl amine solution (356 g, 7.9 moles) and stirred at ambient temperature for 20-24 hrs. After completion of reaction, (checked by TLC). The aqueous layer containing dimethyl amine was separated, and the desired dichloromethane layer was washed twice with water (2 x 200 ml) and charged purified water and adjusted pH to 1-2 with dilute hydrochloric acid, stirred the mixture to separated layers. Finally the dichloromethane layer was distilled out completely to get (S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenyl propan-1-amine hydrochloride (or) crude Dapoxetine hydrochloride.
The crude Dapoxetin hydrochloride was recrystallized in presence of isopropyl alcohol (250 ml) to obtain pure titled compound 65g .
Example-3:
a) Preparation of (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol
To the clean and dry RB flask charged toluene (700 ml), naphthalen-1-ol (85 g, 0.589 moles) and sodium hydroxide (25 g, 0.625 moles) and mixture heated to reflux at 100-115°C and collected water by azeotropic distillation for 2-3 hrs. The reaction mixture was cooled to 25-30°C, followed by addition of (S)-3-chloro-1-phenylpropan-1-ol (100 g, 0.586 moles) and dimethyl sulphoxide (100 ml) at same temperature. The reaction mixture was raised to reflux and maintain for 2-3 hrs. (Checked TLC for completion of reaction.) After completion of reaction water (400 ml) was added and stirred the reaction mixture for 20 min to separate layers. Toluene layer was washed twice with 10% sodium hydroxide solution (150 ml) followed by brine wash. The resultant toluene layer was concentrated (50%) under reduced pressure to obtained (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol.
b) Preparation of (S)-3-(naphthalen-1-yloxy)-1-phenylpropyl para toluene
sulfonate

To the clean and dry RB Flask and charged toluene (500 ml), (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol (100 g, 0.34 moles) and cooled the mixture to 0-5°C. Added triethyl amine (85 gm, 0.841 moles) at 0-5°c followed by addition of p-toluene sulphonyl chloride (120 g, 0.63 moles). The reaction mixture was stirred for 1-2 hrs at 0-5°C, after completion of the reaction water (1000 ml) was added and stirred to separate layers. The resultant aqueous layer was extracted with toluene (300 ml). Combined toluene layer was washed with purified water (200 ml) to get a titled compound.
c) Preparation of (S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenyl propan-1-amine hydrochloride
A solution of (S)-3-(naphthalen-1-yloxy)-1-phenylpropyl p-toluene sulfonate in toluene was added to 40% dimethyl amine solution (356 g ,7.9 moles) and stirred at ambient temperature for 20-24 hrs. After completion of reaction, (checked by TLC). The aqueous layer containing dimethyl amine was separated and the desired toluene layer was washed twice with water (2 x 200 ml) and charged purified water (500 ml) and adjusted pH to 1-2 with dilute hydrochloride, stirred the mixture to separated layers. Finally the toluene layer was distilled out completely to get (S)-N, N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine hydrochloride (or) Dapoxetine hydrochloride
This crude Dapoxetin hydrochloride was recrystallized in presence of isopropyl alcohol (250 ml) to obtain pure titled compound 60 g .
Example:-04
a) Preparation of (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol
To the clean and dry RB flask charged toluene (700 ml), naphthalen-1-ol (85 g, 0.589 moles) and sodium hydroxide (25 g, 0.625 moles) and mixture heated to reflux at 100-115°C and collected water by azeotropic distillation for 2-3 hrs. The reaction mixture was cooled to 25-30°C, followed by addition of (S)-3-chloro-1-phenyl propan-1-ol (100 g, 0.586 moles), and dimethylsulphoxide (100 ml) at same temperature. The reaction mixture was raised to reflux and maintain for 2-3 hrs. (Checked TLC for

completion of reaction.) After completion of reaction water (400 ml) was added and stirred the reaction mixture for 20 min to separate layers. Toluene layer was washed twice with 10% sodium hydroxide solution (150 ml) followed by brine wash. The resultant toluene layer was concentrated (50%) under reduced pressure to obtained (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol.
b) Preparation of (S)-3-(naphthalen-1-yloxy)-1-phenylpropyl para toluene
sulfonate
To the clean and dry RB flask and charged pyridine (300 ml), (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol (100 g, 0.34 moles) and cooled themixture to 0-5°C. Followed by addition of P-toluene sulphonyl chloride (120 g, 0.63 moles) at 0-5°C. The reaction mixture was stirred for 1-2 hrs at 0-5°C, after completion of reaction water (1000 ml) was added and toluene (500 ml) and stirred to separate layers.The resultant aqueous layer was extracted with toluene (300 ml). Combined toluene layer was washed with purified water (200 ml) to get titled product.
c) Preparation of (S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-
1-amine hydrochloride
A solution of (S)-3-(naphthalen-1-yloxy)-1-phenylpropyl p-toluene sulfonate in toluene was added to 40% dimethyl amine solution (356 g, 7.9 moles) and stirred at ambient temperature for 20-24 hrs. After completion of reaction, (checked by TLC). The aqueous layer containing dimethyl amine was separated and the desired toluene layer was washed twice with water (2 x 200 ml) and charged purified water (500 ml) and then adjusted pH to 1-2 with dilute hydrochloride, stirred the mixture to separated layers. Finally the toluene layer was distilled out completely to get (S)-N, N-dimethyl -3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine hydrochloride (or) Dapoxetine hydrochloride.
This crude Dapoxetin hydrochloride was recrystallized in presence of isopropyl alcohol (250 ml) to obtain pure titled compound 67 g .

WE CLAIM:
1. An improved process for the preparation of (S)-Dapoxetine hydrochloride of
formula (I) comprising the steps of;
a) Condensing (S)-3-chloro-1-phenyl propanol of formula (IX) with naphthalene-1-ol (X) in presence of a base to give compound of formula (XI),
b) reacting the compound of formula (XI) with methanesulphonyl chloride in absence of catalyst to produce compound of formula (XII),
c) further the product of step b) is reacting with aqueous dimethyl amine solution in presence of a base to give a compound of formula (XIII) and
d) the isolating Dapoxetine hydrochloride of formula (I).

2. The process as claimed in claim 1, the base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.
3. The process as claimed in claim 1, the solvent is selected from ethyl acetate, THF, isopropyl acetate, isopropyl ether, toluene, methanol, ethanol or isopropyl alcohol.
4. The process as claimed in claim 1, (S)-Dapoxetine hydrochloride having HPLC purity is not less than 99.5%.