FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"PROCESS FOR PREPARING DAPOXETINE HYDROCHLORIDE"
Enaltec Labs Pvt Ltd. an Indian Company, having its Registered Office at 17th,Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS FOR PREPARING DAPOXETINE HYDROCHLORIDE
FIELD OF THE INVENTION:
The present invention relates to a process for preparing Dapoxetine hydrochloride compound of formula I. The process comprises alkylating compound of formula II with an alkylating agent to get a Dapoxetine compound of formula III and then converting Dapoxetine compound of formula III into Dapoxetine hydrochloride compound of formula I.

BACKGROUND OF THE INVENTION:
Dapoxetine hydrochloride is chemically a hydrochloric acid salt of (S)-N, N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine and is known from U.S Patent No. 5,135,947 and is represented by a compound of structural formula I.


Dapoxetine (INN, brand name Priligy) is a short-acting selective serotonin reuptake inhibitor (SSRI) and is marketed for the treatment of premature ejaculation in men.
U.S Patent No. 5,135,947 describes two processes for preparing a racemic compound of structural formula IV.
The first process involves reacting 3-(dimethylarnino)-3-phenylpropan-l-ol compound of structural formula V with naphthalene derivative of structural formula VI in the presence of sodium hydride base to get a compound of structural formula IV.

The second process involves the alkylation of 3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine compound of structural formula VII with an excess of

formaldehyde in the presence of sodium cyano-borohydride and a mutual solvent to get a compound of structural formula IV.

U.S Patent No. 5,135,947 describes that optically active isomers of the racemic compound of structural formula IV may be prepared from their respective optically active precursors or by resolving the racemic mixtures with resolving agents such as optically active tartaric acid,, or 3-bromocamphor-8-sulfonic acid ammonium salt.
U.S Patent No. 5,292,962 describe a process of preparing Dapoxetine hydrochloride compound of structural formula I wherein (R)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of structural formula VIII is reacted with methanesulfonyl chloride in the presence of triethyl amine and dimethylamino pyridine catalyst in tetrahydrofuran solvent to get a compound of structural formula IX, which is reacted with dimethyl amine to get Dapoxetine compound of structural formula III. The Dapoxetine compound of structural formula III is reacted with hydrochloric acid in ethyl acetate to get a Dapoxetine hydrochloride compound of structural formula I.


PCT Publication No.2008/035358 describe a process for the preparation of Dapoxetine hydrochloride compound of structural formula 1 wherein racemic (±) N, N-dimethyl-2-[2-(naphthalenyloxy) ethyl] benzene methanamine is being resolved by chiral acid such as (+)-di-p-toluyl tartaric acid.

O. Torre et ah Tetrahedron Asymmetry 17 (2006) page nos. 860-866 describe the process of preparing Dapoxetine compound of structural formula III by condensing (S)-3-(N,N-Dimethylamino)3-phenylprt)pan-1 -ol compound of

structural formula X and 1-naphthol in the presence of triphenyl phosphine and DEAD catalyst in dry tetrahydrofuran solvent.

This process results impure Dapoxetine compound of structural formula III, this is being purified by flash chromatography technique. Employing flash chromatography technique is tedious and laborious and also involves the use of large quantities of solvents, and hence is not suitable for industrial scale operations.
Accordingly, there is a need in the art to develop a process, which provides pure Dapoxetine compound of structural formula III without flash chromatography technique.
The present invention is directed towards the process of preparing Dapoxetine hydrochloride compound of formula I.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a process for the preparation of Dapoxetine hydrochloride compound of structural formula I comprising the steps of:

a. alkylating a compound of structural formula II with an alkylating agent to get a Dapoxetine compound of structural formula III and

b. converting Dapoxetine compound of formula III into Dapoxetine hydrochloride compound of formula J.

A second aspect of the present invention is to provide a process for the preparation of Dapoxetine hydrochloride compound of structural formula I comprising the steps of:
a. reducing 3-(naphthalen-1-yloxy)-1-phenylpropan-1-one compound of structural formula XI into (R)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of structural formula VIII in the presence of chiral catalyst,


b. converting (R)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of structural formula VIII into (S)-3-(naphthalen-1-yloxy)-l-phenylpropan-1-amine compound of structural formula II,

c. alkylating (S)-3-(naphthalen-1 -yloxy). 1 -phenylpropan-1 -amine
compound of structural formula II with an alkylating agent to get a Dapoxetine compound of structural formula III and


d. converting Dapoxetine compound of structural formula III into Dapoxetine hydrochloride compound of formula I.

A further aspect of the present invention is to provide a process for preparing 3-(naphthaleo-1-yloxy)-1-phoenylpropan-1-one compound of structural formula XI comprises reducing 3-(naphthalen-l-yloxy)-1-phenylprop-2-en-l-one compound of structural formula XII

or oxidizing l-(3-phenylallyloxy) naphthalene compound of structural formula XIII.

The reduction of 3-(naphthalen-l-yloxy)-l-phenylprop-2-en-l-one compound of structural formula XII may be carried out by catalytic hydrogenation.
The example of catalyst may include metal catalyst such as platinum, palladium, rhodium, ruthenium and nickel.
The oxidation of l-(3-phenylallyloxy) naphthalene compound of structural formula XIII may be carried out in the presence of palladium acetate, benzoquinone and perchloric acid in an organic solvent.
A further aspect of the present invention is to provide processes for preparing 3-(naphthalen-1-yloxy)-1-phenylprop-2-en-1-one compound of structural formula XII and l-(3-phenylallyloxy) naphthalene compound of structural formula XIII.
A further aspect of the present invention is to provide a process for preparing l-(3-phenylallyloxy) naphthalene compound of structural formula XIII comprising the condensation of cinnamyl derivative compound of structural formula XTV with naphthol derivative compound of structural formula XV.

Wherein X is leaving group selected from the group comprising of halogen such as chlorine or bromine, hydroxyl group, protected hydroxyl group and Y is also leaving group selected from the group comprising of halogen such as chlorine or bromine, hydroxyl group, protected hydroxyl group with the proviso that when X is a halogen atom then Y is not a halogen atom.

A further aspect of the present invention is to provide compounds of structural formula XI, XII and XIII:

DETAIL DESCRIPTION OF THE INVENTION:
The 3-(naphthalen-1-yloxy)-1 -phenylpropan- 1-one compound of structural formula XI may be prepared by reduction of 3-(naphthalen-l-yloxy)-l-phenylprop-2-en-1-one compound of structural formula XII by catalytic hydrogenation
The 3-(naphthalen-1-yloxy)-1 -phenylpropan-1 -one compound of structural formula XI may also be prepared by oxidation of l-(3-phenylallyloxy) naphthalene compound of structural formula XIII in the presence of palladium acetate, benzoquinone and perchloric acid in an organic solvent.
The reduction of 3-(naphthalen-l-yloxy}-l-phenylpropan-l-one compound of structural formula XI may be carried out by treating 3-(naphthalen-l-yloxy)-l-phenylpropan-1-one compound of structural formula XI with reducing agent in presence of chiral catalyst in polar aprotic solvent at a temperature in the range of -5° to 300C for a period of 2 to 12 hours to get (R)-3-(naphthalen-l-yIoxy)-l-phenylpropan-l-ol compound of structural formula VIII.

The examples of reducing agent may include but not limited to sodium borohydride, borane-tetrahydrofuran (BTHF) or dimethyl sulfide borane (DMSB).
The examples of chiral catalysts may include but not limited to CBS catalyst (Corey-Bakshi-Shibata catalyst), trans-RuCl2 (DMSO) 4 or [Rh (COD) Cl] 2.
The examples of polar aprotic solvents may include but not limited to dichloromethane, tetrahydrofuran ethyl acetate, acetone, dimethyl formamide acetonitrile dimethylsulfoxide or mixture(s) thereof.
The (R)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of structural formula VIII may be isolated by quenching the reaction mixture with 5% hydrogen peroxide and 2N sulfuric acid solution followed the separation of an organic layer.
The organic layer containing (R)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of structural formula VIII may be washed with 2N sulfuric acid solution, 5% sodium metabisulfite solution and 5% aqueous sodium chloride solution.
The organic layer containing (R)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of structural formula VIII may be concentrated under reduced pressure to get (R)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of structural formula VIII.
The (R)-3-(naphthalen-1-yloxy)-1 -phenylpropan-1-ol compound of structural formula VIII may be converted into (S)-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine compound of structural formula II by treating (R)-3-(naphthalen-l-yloxy)-1 -phenylpropan-1 -ol compound of structural formula VIII with methanesulfonyl chloride in the presence of triethyl amine and dimethylamino

pyridine catalyst in tetrahydrofuran solvent at a temperature in the range of 50 -50 to 40°C for a period of 2 to 8 hours and the resulting reaction mixture may be treated with ammonia at a temperature in the range of 00 to 45° C for a period of 4 to 16 hours to get (S)-3-(naphthalen-l-yloxy)-1-phenylpropen-1-amine compound of structural formula II.
The (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine compound of structural formula II may be isolated by quenching the reaction mixture with chilled water and then extract with dichloromethane. The resulting organic layer may be dried over sodium sulfate and concentrated under reduced pressure below 40°C to get (S)-3-(naphthalen-l-yloxy)-1-.phenylpropan-l-amine compound of structural formula II.
The alkylation of (S)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine compound of structural formula II may be carried out by treating (S)-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine compound of structural formula II with alkylating agent in presence of inorganic base in an above mentioned polar aprotic solvent at 0°C to 15°C for a period of 3 hours to 7 hours to get dapoxetine compound of structural formula III.
The alkylating agent is selected from the group comprising of formaldehyde dimethyl sulfate, trimethyl phosphate or methyl iodide
The inorganic base is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
The dapoxetine compound of structural formula III may be isolated by quenching the reaction mixture with water and then extract with dichloromethane. The resulting organic layer washed with 1N hydrochloric acid

and dried over sodium sulfate and then concentrated under reduced pressure below 45°C to get dapoxetine compound of structural formula III.
The dapoxetine compound of structural formula III may be converted into dapoxetine hydrochloride compound of structural formula I by treating a solution of dapoxetine compound of structural formula III in alkyl acetate solution with hydrochloric acid solution in an alkyl acetate solvent at a temperature in the range of 0°C to 30C for a period of 30 minutes to 6 hours to get dapoxetine hydrochloride compound of structural formula I.
The examples of alkyl acetate solvents may be selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof.
The hydrochloric acid solution in alkyl acetate solvent may contain hydrochloric acid in the range of 5% weight / weight to 15% weight / weight.
The dapoxetine hydrochloride compound of structural formula I may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.
The isolated dapoxetine hydrochloride compound of structural formula I may be dried at a temperature in the range of 40°C to 150°C for a period of 2 hours to 8 hours under reduced pressure.
EXAMPLES
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

Example: Preparation of dapoxetine hydrochloride.
Step-1: Preparation of (R)-3-(naphthalen-1 -yloxy)- 1-phenylpropan- l-ol compound of structural formula VIII
A solution of 3-(naphthalen-1 -yloxy)-1-phenylpropan-1-one compound of structural formula XI (50gm) in dichloromethane (500ml) was added borane-dimethyl sulfide (14ml) and Corey-Bakshi-Shibata catalyst (3ml) at 0-10°C for a period of 5 hours. The resulting reaction mixture was stirred for 2 hours at 5-10°C and then the reaction mixture was quenched with a mixture of hydrogen peroxide (5%, 100ml) and sulfuric acid solution (2N, 6ml). The dichloromethane layer separated, washed separately with sulfuric acid solution (2N, 100ml), sodium metabisulflte solution (5%, 250ml), aqueous sodium chloride solution (5%, 250ml) and then resulting dichloromethane layer was concentrated under reduced pressure to get title compound. Yield: 49gm
Step-2: Preparation of (S)-3-(naphthalen-1 -yloxy)-1 -phenylpropan-1 -amine compound of structural formula II
A solution of (R)-3-(naphthalen-1-yloxy)-1 -phenylpropan-1-ol compound of structural formula VIII (20gm) in tetrahydrofuran (200ml) was added methanesulfonyl chloride (8.5gm), triethyl amine (7.5gm) and dimethylamino pyridine (2.5mg) at 0-5°C and stirred for 6 hours at same temperature. The resulting reaction mixture was then purged with ammonia gas for 6 hours at 0-5°C followed by stirred for 12 hours at 25-35°C and then the reaction mixture was quenched with chilled water (300ml) and extracted with dichloromethane (400ml). The dichloromethane layer was dried over sodium sulfate (20gm) and then concentrated under reduced pressure below 40°C to get title compound. Yield: 19.5gm

Step-3: Preparation of dapoxetine compound of structural formula III A solution of (S)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine compound of structural formula II (15gm) in dichloromethane (180ml) was added methyl iodide (7.6gm), sodium hydroxide (3.0gm) and the resulting reaction mixture was stirred for 6 hours at a temperature 0-10°C and then the reaction mixture was then quenched with water (250ml) and extracted with dichloromethane (300ml). The dichloromethane layer was washed with IN hydrochloric acid (50ml), dried over sodium sulfate (l0gm) and concentrated under reduced pressure below 45°C to get title compound. Yield: 16.5gm
Step-4: Preparation of dapoxetine hydrochloride compound of structural
formula I.
Dapoxetine (l0gm) was dissolved in ethyl acetate (100ml) at 25-30°C and then
it was cooled to 5-10°C. The resulting solution was then added hydrochloric
acid solution in ethyl acetate (30ml, 8% weight / weight) drop wise within 1
hour and the resulting reaction mixture was stirred for 1 hour at 5-10°C. The
resulting solids were filtered, washed with chilled ethyl acetate (10ml) and dried
at 45-50°C for 4 hours to get title compound.
Yield: ll.lgrn
Purity: 99.98% (By HPLC)

WE CLAIM:
1. A process for the preparation of Dapoxetine hydrochloride compound of structural formula I comprising the steps of:
a. alkylating a compound of structural formula II with an alkylating agent to get a Dapoxetine compound of structural formula III and

b. converting Dapoxetine compound of formula III into Dapoxetine hydrochloride compound of formula I.

2. A process for the preparation of Dapoxetine hydrochloride compound of
structural formula I comprising the steps of:
a. reducing 3-(naphthalen-l-yloxy)-l-phenylpropan-l-one compound of structural formula XI into (R)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of structural formula VIII in the presence of chiral catalyst,


b. converting (R)-3-(naphthalen-l-yloxy)-1-phenylpropan-l-ol compound of structural formula VIII into (S)-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine compound of structural formula II,

c. alkylating (S)-3-(naphthalen-1 -yloxy)-1-phenylpropan-1 -amine
compound of structural formula II with an alkylating agent to get a Dapoxetine compound of structural formula III and


d. converting Dapoxetine compound of structural formula III into Dapoxetine hydrochloride compound of formula I.

3. The process according to claim no. 2 wherein reduction of 3-(naphthalen-l-yloxy)-l-phenylpropan-l-one compound of structural formula XI is carried out by reducing agent such as sodium borohydride, borane-tetrahydrofuran (BTHF) or dimethyl sulfide borane (DMSB) in the presence of chiral catalyst such as CBS catalyst (Corey-Bakshi-Shibata catalyst), trans-RuCl2 (DMSO) 4 or [Rh (COD) Cl2 in polar aprotic solvent such as dichloromethane, tetrahydrofuran ethyl acetate, acetone, dimethyl formamide acetonitrile dimethylsulfoxide or mixture(s) thereof.
4. The process according to claim no. 2 wherein (R)-3-(naphthalen-1-yloxy)-l-phenylpropan-1-ol compound of structural formula VIII is converted into (S)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine compound of structural formula II by treating (R)-3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol compound of structural formula VIII with methanesulfonyl chloride in the presence of triethyl amine and dimethylamino pyridine catalyst in tetrahydrofuran solvent at a temperature in the range of -5° to 40°C for a period of 2 to 8 hours and the resulting reaction mixture is treated with ammonia at a temperature in the range of 0° to 45° C for a period of 4 to 16 hours to get (S)-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine compound of structural formula II.

converting (R)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of structural formula VIII into (S)-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine compound of structural formula II
5. A process for preparing 3-(naphthalen-1-yloxy)-1-phenylpropan-1-one compound of structural formula XI comprises reducing 3-(naphthalen-l-yloxy)-l-phenylprop-2-en-l-one compound of structural formula XII

or oxidizing l-(3-phenylallyloxy) naphthalene compound of structural formula XIII.

6. The process according to claim no. 5, wherein reduction of 3-(naphthalen-l-yloxy)-l-phenylprop-2-en-l-one compound of structural formula XII is carried out by catalytic hydrogenation in the presence of metal catalyst such as platinum, palladium, rhodium, ruthenium and nickel and oxidation of l-(3-

phenylallyloxy) naphthalene compound of structural formula XIII is carried out in the presence of palladium acetate, benzoquinone and perchloric acid.
7. A process for preparing l-(3-phenylallyloxy) naphthalene compound of structural formula XIII comprising the condensation of cinnamyl derivative compound of structural formula XIV with naphthol derivative compound of structural formula XV.

Wherein X is leaving group selected from the group comprising of halogen such as chlorine or bromine, hydroxyl group, protected hydroxyl group and Y is also leaving group selected from the group comprising of halogen such as chlorine or bromine, hydroxyl group, protected hydroxyl group with the proviso that when X is a halogen atom then Y is not a halogen atom.
8. A compounds of structural formula XI, XII and XIII:


9. The use of compounds of structural formula XI, XII and XIII for the
preparation of Dapoxetine hydrochloride compound of formula I.
10. The process according to claim nos 1 and 2 wherein alkylation of
compound of structural formula II is carried out by alkylating agent such as
formaldehyde dimethyl sulfate, trimethyl phosphate or methyl iodide.