Field of invention:

The present invention relates to a cost effective and eco-friendly process for the preparation of Dapoxetine, chemically known as S (+)-N,N-dimethyl-l-phenyl-3(l-naphthalenenyloxy) propanamine Hydrochloride with high yield and purity. Further, present invention provides process for recovering Racemic (±) Dapoxetine and its acid addition salts from mother liquors containing salts of unwanted R(-) enantiomer.

Background of the invention:

It has been suggested that premature ejaculation (PE) is associated with perturbations in serotonergic 5-hydroxytryptamine (5-HT) neurotransmission. PE caused by decreased central serotonergic signaling, hyposensitivity of the 5-HT2C receptor, or hypersensitivity of the 5-HTi A receptor, all of which decrease ejaculatory latency time in animal model systems. PE is a common problem, which is associated with considerable anxiety, frustration, and negative impact on affected men and their sexual partners. No pharmaceutical agents have been approved for this indication. However, therapies that target 5-HT neurotransmission, such as selective serotonin reuptake inhibitor (SSRI) anti¬depressants, have been used in this setting with varying efficacy and tolerability.

Dapoxetine is the first agent to be developed specifically to treat PE. This agent significantly prolongs Intravaginal ejaculation latency time (IELT) and increases the sense of control and sexual satisfaction for men with PE and their partners. Dapoxetine is well tolerated, with a favorable pharmacokinetic profile that allows for on-demand use. Dapoxetine hydrochloride is an SSRI with a short half-life developed specifically for the treatment of men with PE, but is slightly different from the SSRIs. (S)- (+)-Dapoxetine hydrochloride, a potent SSRI with a short half-life, marked under trade name, Priligy has been developed specifically for the treatment of PE. This substance was first launched in2009 in Europe where it is used for the oral, on-demand treatment of PE in men between 18 and 64 years of age.

Dapoxetine is chemically known as S-(+) - N, N-di methyl-[3-(naphthalen-l-yloxy)-l-phenylpropyl] amine.

Dapoxetine is first disclosed in patent No. EP 0288188. The patent Provides process for the preparation of various l-phenyl-3-naphthalenyloxypropanamines along with their pharmaceutically acceptable salts, and their resolution into optically active enantiomers with (+), (-) tartaric acid by performing seven recrystalizations described. Dapoxetine is one
among the various phenyl-3-naphthalenyloxy propanamines described.

US patent No. 5,135,947 also discloses various l-phenyl-3-naphthalenyloxypropanamines and their use as selective serotonin receptive inhibitors.

US Patent No. 5292692 discloses novel intermediates to l-phenyl-3-naphthalenyloxy propanamines i.e. through 1, 3- dihydroxy compounds.

US patent 5023269 and US 4956388 discloses about 3-aryl oxy-3-substituted propanamines.

WO 2008/035358 discloses resolution of Racemic (±) Dapoxetine with a chiral acid such as (+) di-p-toluyl tartaric acid and further conversion into its acid addition salts.

The processes of prior art use dimethylamine gas or generate gaseous Dimethyl amine by potassium hydroxide in the conversion of 3-chloro-l-phenyl-1-propan-l-ol of formula
(III) to Racemic Dapoxetine. This method is cumbersome and unsuited to large scale production.

Processes of prior art suffer from the draw back of low yields as 'R' Dapoxetine is discarded. This adds to the cost and is also an environmental hazard.

The aforesaid processes though discloses the preparation of Dapoxetine and its pharmaceutically acceptable salts , however the consumption of the ingredients is high, leading to high cost of the process, also yields are low, develops waste by products and is not environmentally friendly.

In view of the above drawbacks, there is still a need in the art to provide an eco-friendly and economical process for preparation of Dapoxetine (Formula I) and its pharmaceutically acceptable salts in high yield and purity by recycling the recovered Racemic (±) Dapoxetine intermediate (Formula II). The instant invention further reports a process that uses aqueous Dimethyl amine in a two phase reaction to obtain Dapoxetine free base.

OBJECT OF THE INVENTION:

In accordance with the above, the primary objective of the present invention is to provide an improved and economically feasible continuous process for the preparation of S (+) Dapoxetine (Formula-I) and its salts with high yield and purity by resolving Racemic (±) Dapoxetine (Formula-II) with optimum utilization of materials by recovering Racemic (±) Dapoxetine.

Another objective of the invention is to provide a process for the recovery of Racemic (±) Dapoxetine (Formula-II) from mother liquor containing acid salts of R and S- Dapoxetine and to resolve recovered racemic (±) Dapoxetine to obtain S-Dapoxetine (Formula-I) and its salts with high yield and purity.

Another object of the present invention is to provide process for the preparation of Racemic Dapoxetine from 3-chloro-l-phenyl-1-propan-l-ol [ formula(III) ] by using aqueous Dimethylamine in a two phase reaction to obtain Dapoxetine further formation of its acid addition salt with oxalic acid.

SUMMARY OF THE INVENTION:

The present invention provides a cost-effective and feasible, Process for the preparation of S-Dapoxetine and its pharmaceutically acceptable salts.

In a preferred aspect, the present invention provides a continuous process for the preparation of Dapoxetine (Formula-I) and its salts with high yield and purity comprising:

i) Resolving Racemic (±)Dapoxetine(Formula-II) with D(-) Tartaric acid in presence of suitable solvent to obtain acid salt of enriched S-Dapoxetine;

ii) Converting enanatiomerically pure salt of enriched S-Dapoxetine from (step - i) into optically pure S-Dapoxetine by treating with base in presence of water and water immiscible solvent followed by convertion into its acid addition salts;

iii) Recovering the racemic (±) Dapoxetine (Formula-II) from mother liquor enriched with R and small amounts of S-Dapoxetine acid salts by treating with a base in presence of water and water immiscible solvent; and

iv) Resolving the racemic (±) Dapoxetine (Formula-II) from (step- iii) in presence of D (-) Tartaric acid and suitable solvent to obtain optically pure S (+) Dapoxetine and converting into its acid addition salts.

Another aspect of the present invention provides a process for the preparation of S (-) Dapoxetine (Formula-I) and its salts with high yield and purity comprising

i) Resolving racemic (±)Dapoxetine (Formula-I!) with natural L(+) Tartaric acid in presence of suitable solvent by separating a solid phase comprising an acid salt of enriched R(-)
ii) Dapoxetine;

ii) Isolating the enriched S (+) Dapoxetine from mother liquor in presence of suitable solvent;

iii) Converting enanatiomerically pure salt of enriched S-Dapoxetine from (step - ii) by treating with base in presence of water and water immiscible solvent and converting into its acid addition salts.

In the final aspect, of the present invention provides process for the preparation of Racemic Dapoxetine (Formula-II) and its acid addition salts with high purity comprising

i) condensing 3-chloro-1-phenyl-propan-1-ol (Formula-Ill) with a-naphthol in presence of phase transfer catalyst in suitable solvent to afford 3-(Naphthalen-l-yloxy)-l-phenyl-propan-1-ol (Formula IV);

ii) reacting 3-(Naphthalen-l-yloxy)-l-phenyl-propan-l-ol (Formula IV ) with methane sulphonyl chloride in presence of suitable base in suitable organic solvent to obtain compound of formula V;

iii) treating the compound of formula V with aqueous Dimethyl amine in the presence of phase transfer catalyst to afford racemic Dapoxetine (Formula-II) in crude form and

iv) Dissolving crude Racemic Dapoxetine (Formula-II) in suitable organic solvent followed by treatment with organic acid to form Racemic Dapoxetine acid addition salts in pure form with high yield.

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. The embodiments as described are not limiting or restricting the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a cost-effective and feasible, Process for the preparation of S-Dapoxetine and its pharmaceutically acceptable salts.

In a preferred aspect, the present invention provides a process for the preparation of S (+) Dapoxetine (Formula-I) and its salts with high yield and purity comprising:

i) Resolving Racemic (±)Dapoxetine (Formula-II) with D(-) Tartaric acid in presence of suitable solvent to obtain acid salt of enriched S-Dapoxetine;

ii) Converting enanatiomerically pure salt of enriched S-Dapoxetine from (step-i) into optically pure S-Dapoxetine by treating with base in presence of water and water immiscible solvent and converting into its acid addition salts;

iii) Recovering the racemic (±) Dapoxetine (Formula-II) from mother liquor enriched with R and small amounts of S-Dapoxetine acid salts by treating with a base in presence of water and water immiscible solvent;

iv) Resolving the racemic (±) Dapoxetine (Formula-II) from (step iii) in presence of D (-) Tartaric acid and suitable solvent to obtain optically pure S (+) Dapoxetine and converting into its acid addition salts.

The term 'racemic Dapoxetine' means a 1:1 mixture of R-and S-Dapoxetine or one of the
enantiomers may be slightly in excess with specific rotation close to zero.
In one of the embodiment, the process for resolution of racemic Dapoxetine (Formula II) comprises following steps:

i) resolving racemic (±)Dapoxetine (Formula-II) with D(-) Tartaric acid in presence of suitable solvent to obtain acid salt of enriched S-Dapoxetine;

ii) Converting enanatiomerically pure salt of enriched S-Dapoxetine from (step-i) into optically pure S-Dapoxetine by treating with base in presence of water and water immiscible solvent and converting into its acid addition salts.

Accordingly, the racemic Dapoxetine (Formula II) is treated with pure optically active acid in solvent to get enanatiomerically pure S-Dapoxetine. The optically active acid used is here D (+) tartaric acid in sub molar quantity ranging from 0.40 - 0.90 mole/mole of Racemic Dapoxetine. The reaction is carried out in a solvent selected from group consisting of C1-C4 alcohols such as methanol, ethanol, isopropyl alcohol and butyl alcohol; acetonitrile; acetone or mixture thereof with water, preferably aqueous isopropanol and aqueous Acetonitrile with 5-15% of water. The reaction is firstly carried out at a temperature ranging from 40°C to 60°C and then at a temperature of 20-30°C for period of 2-6hrs. The reaction mixture is cooled to 20-25C. After cooling, the precipitated salt is filtered to get compound with a chiral purity of greater than 99%.

The enanatiomerically pure active acid salt of S-Dapoxetine thus obtained is treated with base in presence of water and water immiscible solvent to obtain Dapoxetine free base as oily in enanatiomerically pure form. The base used herein is selected from the group consisting of organic and inorganic base; the organic bases are selected from triethylamine, diisopropyl ethyl amine, pyridine, piperidine, while the inorganic bases are selected from the group consisting of alkali metal carbonates, bicarbonates, and their hydroxides or liquor ammonia.
The reaction is carried out at a basic pH range of 8.0-12.0 and at temperature of 20-25°C. The resulting solution is extracted with water immiscible organic solvents to get optically pure S (+) Dapoxetine (Formula I). The water immiscible organic solvents used herein are selected from the group consisting of toluene, chloroform, dichloromethane, Ethyl acetate and more preferably dichloromethane and Ethyl acetate. Further, obtained organic layer is subjected to distillation to obtain S(+)Dapoxetine free base (Formula-I) that can be converted into its desired pharmaceutically acceptable acid addition salt using conventional techniques by reacting with a pharmaceutically acceptable acid. Pharmaceutically acceptable acids that can be used for preparing the salt of Dapoxetine is preferably Hydrochloric acid. The crystalline S(-) Dapoxetine acid addition salt can be prepared in suitable solvent selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, or mixtures thereof, preferably isopropyl alcohol and ethyl acetate. The amount of acid used herein is 1.0 to 1.1 equivalents to the Dapoxetine free base. The reaction mixture is stirred for 5-8hrs, at 20-25°c and further cooled to 0-5°c. The separated acid addition salts are filtered and washed with solvent to get pure S (+) Dapoxetine acid addition salt.

In another embodiment, the present invention provides a process for recovering the racemic Dapoxetine from the mother liquor enriched with R-Dapoxetine salt, which leads to more yield of S(+)Dapoxetine ( Formula I) by utmost utilization of racemic Dapoxetine( Formula II), comprising steps of;

i) Collecting the mother liquor enriched with tartaric acid salt of R- Dapoxetine and small amount of tartaric salt of S-Dapoxetine.

ii) Concentrating the liquid phase of step-i and reacting with inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia and organic base like triethylamine to obtain free racemic Dapoxetine base (formula-II).

iii) Extracting the racemic Dapoxetine(formula-II) of step (ii) in suitable organic solvents;

iv) concentrating the extracted phase and converting into its acid addition salt with oxalic acid in presence of suitable solvent;

v) Resolving recovered Dapoxetine (step IV) with D (-) Tartaric acid, in suitable solvent to obtain acid salt of enriched Dapoxetine in optically pure form, followed by converting into its acid addition salts.

According to the process, the mother liquor obtained after isolating the resolved S-Dapoxetine salts is collected and further subjected to distillation under reduced pressure. The above obtained residual mass is converted into racemic Dapoxetine by treating with base in a presence of water and water immiscible solvent. The base used herein is selected from the group consisting of organic and inorganic bases; organic bases are selected from triethyl amine, diisopropyl ethyl amine, pyridine, piperidine; preferably triethyl amine and inorganic bases are selected from the group of alkali metal carbonates like sodium carbonate, potassium carbonate, and their hydroxides like sodium hydroxide, potassium hydroxide and liquid ammonia; preferably sodium hydroxide or potassium hydroxide. The reaction is carried out at a basic pH range of 9-13, and at temperature of 20-25°C, the resulting solution is further extracted with water immiscible organic solvents to get the racemic Dapoxetine compound. The water immiscible organic solvents used here are selected from the group consisting of toluene, xylene, ethyl acetate, chloroform, dichloroethane and dichloromethane; preferably dichloromethane, toluene, and ethyl acetate. The extracted phase is subjected to distillation to obtain an oily residue, which may be dissolved in another suitable solvent. Solvent may be removed by distillation with or without vacuum at elevated temperatures such as 25-60°C. The racemic Dapoxetine thus obtained can be converted into its acid addition salt using conventional techniques.

Acids that can be used for preparing the salt of racemic Dapoxetine are preferably oxalic acid. The crystalline racemic Dapoxetine (Formula-II) acid addition salt can be prepared in suitable solvent selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, or mixtures thereof, preferably Isopropyl alcohol. The amount of acid used herein is 1.0 to 1.1 equivalents to the Dapoxetine base. The reaction mixture is stirred for 5-8hrs, at 20-25°c and further cooled to 10-15°c. The separated acid addition salts are filtered and washed with solvent to get pure Racemic Dapoxetine acid addition salt. Recovered racemic Dapoxetine from the above process is having purity more than 99% w/w as determined by HPLC as well as chiral purity shows 1:1 ratio of R & S isomers which is further converted into optically active Dapoxetine and its acid addition salts in high yield.

Another aspect of the present invention provides a process for the preparation of S (-) Dapoxetine (Formula-I) and its salts with high yield and purity comprising

i) Resolving Racemic (±)Dapoxetine (Formula-II) with natural L(+) Tartaric acid in presence of suitable solvent followed by separating a solid phase comprising an acid salt of enriched R(-) Dapoxetine;

ii) Isolating the enriched S (+) Dapoxetine from mother liquor in presence of suitable solvent.

iii) Converting enanatiomerically pure salt of enriched S-Dapoxetine from (step - ii) by treating with base in presence of water and water immiscible solvent and converting into its acid addition salts.

Accordingly, the Racemic Dapoxetine (Formula II) is treated with pure optically active acid in solvent to get enanatiomerically pure S-Dapoxetine. The optically active acid used is here L (+) tartaric acid in sub molar quantity ranging from 0.40 - 0.90. The reaction is carried out in a solvent selected from group consisting of C1-C4 alcohols such as methanol, ethanol, isopropyl alcohol and butyl alcohol; acetonitrile; acetone or mixture with water thereof, preferably aqueous isopropanol and aqueous Acetonitrile with 5-15% of water. The reaction is firstly carried out at a temperature ranging from 40°C to 60°C and then at a temperature of 20-30°C for period of 2-4hrs. The reaction mixture is cooled to 20-25°C. After cooling, the precipitated salt is filtered to get solid phase comprising predominantly a salt of (+) Tartaric acid with R (-) enantiomer of the Dapoxetine.

Further liquid phase is collected and subjected to under vacuum at elevated temperatures. Obtained residue is triturated with suitable solvent selected from group consisting of C1 -CA alcohols such as methanol, ethanol, isopropyl alcohol and butyl alcohol; acetonitrile; acetone or mixture with water thereof, preferably aqueous isopropanol and aqueous Acetonitrile with 5-15% of water. The reaction is carried out at a temperature ranging from 20-30°C for period of 2-4hrs. The reaction mixture is cooled to 20-25°C. After cooling, the precipitated salt is filtered to get compound with a chiral purity of greater than 99%.

Thus obtained above pure compound is further converted to S(+) Dapoxetine and its acid addition salts as mentioned above.

One of the aspects of the present invention provides process for the preparation of racemic Dapoxetine (Formula-II), which comprises,

i) condensing 3-chloro-l-phenyl-propan-l-ol (Formula-Ill) with a-naphthol in presence of phase transfer catalyst suitable solvent to afford 3-(Naphthalen-l-yloxy)-l-phenyl-propan-1-ol (Formula IV)

ii) reacting 3-(Naphthalen-l-yloxy)-l-phenyl-propan-l-ol (Formula IV ) with methane sulphonyl chloride in presence of suitable base in suitable organic solvent to obtain compound of formula V;

iii) treating the compound of formula V with aqueous Dimethyl amine in the presence of phase transfer catalyst to afford Racemic Dapoxetine (Formula-II) in crude form and

iv) Dissolving Racemic Dapoxetine (Formula-II) in suitable organic solvent and treating with organic acid to form Racemic Dapoxetine acid addition salt in pure form with high yield.
The process for the preparation of S (-) Dapoxetine of formula (I) is described in below stated scheme - 1

According to this aspect, 3-chloro-l-phenyl-propan-l-ol (Formula-Ill) is condensed with a-naphthol in presence of suitable base like Potassium hydroxide, sodium hydroxide . by using phase transfer catalyst like tetra butyl ammonium bromide, tetra propyl ammonium bromide, tri butyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulphate, benzyl trimethyl ammonium bromide, benzyl triethyl ammonium chloride, ethyl tri phenyl phosphonium bromide more preferably tetra butyl ammonium bromide (TBAB) and in a solvent like water to afford 3-(Naphthalen-l-yloxy)-l-phenyl-propan-l-ol. The reaction can be carried out at 60-100°c, preferably 70-80°c, and extracted with water immiscible solvent like methylene dichloride, ethylene di chloride, Toluene, Ethyl acetate preferably toluene.

Extracted organic layer is subjected to distillation to obtain 3-(Naphthalen-l-yloxy)-l-phenyl-propan-1-ol (Formula IV) as oily residue.

The above 3-(Naphthalen-l-yloxy)-l-phenyl-propan-l-ol (Formula IV ) is reacted with methanesulfonyl chloride by using Triethylamine as a base in suitable solvent like methylene dichloride at suitable temperature -5to +5°c for 4-8 hrs. After completion of reaction, the reaction mass was treated with aqueous Dimethyl amine Solution in the presence of phase transfer catalyst like tetra butyl ammonium bromide, tetra propyl ammonium bromide, tri butyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulphate, benzyl trimethyl ammonium bromide, benzyl triethyl ammonium chloride, ethyl tri phenyl phosphonium bromide more preferably tetra butyl ammonium bromide (TBAB) and stirred for 24-48 hrs at room temperature. After completion of conversion, separated organic layer; subjected to distillation and further converted into its oxalate salt in suitable solvent. This can be prepared in suitable solvent selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, or mixtures thereof, preferably Isopropyl alcohol. The amount of acid used herein is 1.0 to 1.1 equivalents to the Dapoxetine free base. The reaction mixture is stirred for 3-4hrs, at 20-25°c and further cooled to 10-15°c. The separated acid addition salt is filtered and washed with solvent to get pure form Racemic Dapoxetine acid addition salt. Recovered Racemic Dapoxetine from the above process is having purity more than 99% w/w as determined by HPLC as well as chiral purity shows 1:1 ratio of R & S isomers which is further converted into optically active Dapoxetine and its acid addition salts in high yield.

Having thus described the present invention with reference to particular embodiments, those skilled in the art will appreciate modifications that do not depart from the spirit and scope of the disclosure. The following examples are set forth to further describe certain specific aspects and embodiments but are not intended to, and should not be construed to, be limiting in any way. The examples do not include detailed descriptions of conventional methods; as such methods are well known to those of ordinary skill in the art and are described in numerous publications.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown by way of example, for purpose of illustrative discussion of preferred embodiments of the invention, and are not limiting the scope of the invention

Examples:
Example -1

Process for the preparation of 3-(Naphthalen-1 -y low)-1 -phenyl-propan-1 –o1:-
70 gm of a-Naphthol was charged to the mixture of sodium hydroxide (32gm) and water
(200ml) in a round bottom flask at 25-35°c under stirring. To this solution Tetra butyl
ammonium bromide TBAB (3gm) added and raised to 70-80°c.l00gm of 3-chloro-!-
phenyl-propan-1-ol slowly added for 1-2 firs and reaction mass was maintained for 6-8hrs
at 70-80°c. After completion of TLC, the mass was cooled to room temperature and
extracted with Toluene (500ml).

The layers were separated and washed the organic layer with water (200ml) and the.
Separated organic layer distilled under vacuum to obtain as oil.

Example -2
Process for the preparation of N,N-dimethyl-l-phenyl-3-(l-naphthalenyloxy) propanamine oxalate ( Racemic Dapoxetine oxalate )
100gm of 3-(Naphthalen-l-yloxy)-l-phenyl-propan-1-of. 75 gm of Triethyl amine was placed in 1000 ml of Methylene di chloride in a round bottom flask under stirring at 25-35°c. Methane sulofonyl chloride (60gm) was added to reaction mixture over a period of 1.0-2.0 hrs at -2 to-5°c and maintained for 5-6 hrs at the same temperature. After completion of reaction. Aqueous Dimethyl amine solution (450ml) and TBAB (5gm) were added at 0-10°c. Maintained for 35-40 hrs at 25-35°c. After completion of reaction on TLC, separated organic Saver and washed with water. Separated organic layei was subjected to distillation to obtain Racemic Dapoxeline as oil. which was dissolved in Acetonitrile (200ml); treated with charcoal (l0gm) at 45-50° C and filtered through Hyflow. Collected the filtrate and charged Oxalic acid (35gm). The mixture was stirred for 10-12 hours at 20-25° C. The formed solid was filtered off, washed with Acetonitrile (25ml) to attain 98gm of title compound with purity by HPLC is 99.88%.

Example 3
Process for the preparation of (+)-N,N-dimethyl-l-phenvl-3-(l-naphthalenyloxy) propanamine D (-) tartaric acid salt.(S-Dapoxetine Tartarate)

100 gm of the N, N-dimethyl-l-phenyl-3-(l-naphthalenyloxy) propanamine oxalate was suspended in mixture of methylene dichloride and water in a round bottom flask. Ammonia was added to attain pH 8.0-9.0. The layers were separated. The separated aqueous layer was extracted with methylene di chloride. The organic layers were washed with water (200ml). The solvent was evaporated under reduced pressure to obtain oil which was dissolved in Isopropyl alcohol(600) at 40-45°c followed by the addition of 17 gm of D(-) Tartaric acid in water(90ml). The reaction mass was maintained for 2-3 hrs at 40-45°c. The mixture further cooled to 25-30°C and maintained for 3-5hrs at the same temperature. Filtered the solid and washed the compound and dried to attain 35-40gm of the title compound having above 99.0% of chiral purity.

Example 4
Process for the preparation of (+)-N, N-dimethyl-l-phenyl-3-(l-naphthalenyloxy) propanamine (S-Dapoxetine Tartarate)
100 gm of the N, N-dimethyl-l-phenyl-3-(l-naphthalenyloxy) propanamine oxalate was suspended in mixture of methylene dichloride and water in a round bottom flask. Ammonia was added to attain pH 8.0-9.0. The layers were separated. The separated aqueous layer was extracted with methylene di chloride. The organic layers were washed with water (200ml). The solvent was evaporated under reduced pressure to obtain oil which was dissolved in Acetonitrile (600) at 40-45°c followed by the addition of 35 gm of L(+) Tartaric acid in water(90ml). The reaction mass was maintained for 2-3 hrs at 40-45°c. The mixture further cooled to 25-30°C and maintained for 3-5hrs at the same temperature. Filtered the solid and washed the compound and dried to attain 35-40gm of the enriched R (-) Dapoxetine Tartarate. Further collected liquid phase and distilled under reduced pressure. The obtained residual mass is triturated with Isopropyl alcohol and cooled to 20-25°c. Maintained the mass for 2-3 hrs and filtered to obtain pure S (+) Dapoxetine Tartarate and dried.

Example 5
Preparation of S-Dapoxetine Hydrochloride
A salt of (+)-N, N-dimethyl-l-phenyl-3-(l-naphthalenyloxy) propanamine D (-) tartaric acid salt(S-Dapoxetine Tartarate) (50gm) was mixed with methylene dichloride (400ml) and water (400ml) in a round bottom flask. Dilute sodium Hydroxide solution was added to attain pH 9.0-10.0. The layers were separated. The separated aqueous layer was extracted with methylene dichloride (300ml). The organic layers were washed with water (300ml). The organic layer was dried with sodium sulphate. The solvent was evaporated under reduced pressure to obtain oil which was dissolved in Isopropyl Alcohol (200ml). Further treated with charcoal (5gm) at 45-50° C and filtered through hyflow. Collected the filtrate and acidified with Hydrochloric acid in Isopropyl Alcohol. The mixture was stirred for 3-4 hours at 20-25° C. The mixture was cooled to 0-5°C and stirred for 1-2 hours. The formed solid was filtered off, washed with Isopropyl Alcohol (25ml) to attain 35gm of title compound with chiral purity above 99.00% and purity by HPLC is 99.78%.

Example 6
Recovery of Racemic Dapoxetine from mother liquors of (+)-N,N-dimethyl-l-phenyl-3-(l-naphthalenyloxy')propanamine D (-)tartaric acid salt.(S-Dapoxetine Tartarate) and conversion to Racemic Dapoxetine oxalate
Collected mother liquor of (+)-N,N-dimethyl-l-phenyl-3-(l-
naphthalenyloxy)propanamine D (-)tartaric acid salt.(S-Dapoxetine Tartarate) enriched with (R) - Dapoxetine Tartarate distilled off the solvent under reduced pressure at 55-60°C to obtain syrupy mass. The syrupy mass was diluted with water (300ml) and
adjusted pH 11.5-12.5 with sodium hydroxide solution. The reaction mass was stirred for
30-60 min at room temperature. Further extracted with dichloromethane (300ml) twice.
Combined all organic layers and washed with water (250ml). The layers were separated.
The solvent was evaporated under reduced pressure to obtain oil which was dissolved in
Isopropyl alcohol (50ml) and solvent stripped off. The residual mass was dissolved in
Isopropyl alcohol (50ml) and stirred for 15 minuites at 25-30°C.Acidified with oxalic
acid .The reaction mass was stirred for 5-6 hrs at the same temperature. The solid was
filtered off and washed the compound with Isopropyl alcohol (50ml). Dried the solid at
40-50°C to attain Racemic Dapoxetine oxalate 35-40 gm of the Purity by HPLC -
99.86%, S.O.R. - ±0.5°

Example 7
Collected mother liquor of (+)-N,N-dimethyl-l-phenyl-3-(l-
naphthalenyloxy)propanamine D (-)tartaric acid salt.(S-Dapoxetine Tartarate), enriched with (R) - Dapoxetine Tartarate, distilled off the solvent under reduced pressure at 55-60°C to obtain syrupy mass. The syrupy mass was diluted with water (300ml) and adjusted pH 8.5-9.5 with Ammonia solution. The reaction mass was stirred for 30-60 min at room temperature. Further extracted with Ethyl acetate (300ml) twice. Combined all organic layers and washed with water (250ml). The layers were separated. The solvent was evaporated under reduced pressure to obtain oil which was dissolved in Isopropyl alcohol (50ml) and solvent stripped off. The residual mass was dissolved in Isopropyl alcohol (50ml) and stirred for 15 minutes at 25-30°C.Acidified with oxalic acid .The reaction mass was stirred for 5-6 hrs at the same temperature. The solid was filtered off and washed the compound with Isopropyl alcohol (50ml). Dried the solid at 40-50°C to attain Racemic Dapoxetine oxalate 35-40 gm of the Purity by HPLC - 99.68%. S.O.R. -±0.5°

Example 8
Collected mother liquor of (+)-N,N-dimethyl-l-phenyl-3-(l-
naphthalenyloxy)propanamine D (-)tartaric acid saJt.(S-Dapoxetine Tartarate) enriched
with (R) - Dapoxetine Tartarate, distilled off the solvent under reduced pressure at 55-60°C to obtain syrupy mass. The syrupy mass was diluted with water (300ml) and adjusted pH 11.5-12.5 with Triethylamine solution. The reaction mass was stirred for 30-60 min at room temperature. Further extracted with methylene dichloride (300ml) twice. Combined all organic layers and washed with water (250ml). The layers were separated. The solvent was evaporated under reduced pressure to obtain oil which was dissolved in Isopropyl alcohol (50ml) and solvent stripped off. The residual mass was dissolved in Isopropyl alcohol (50ml) and stirred for 15 minutes at 25-30°C.Acidified with oxalic acid .The reaction mass was stirred for 5-6 hrs at the same temperature. The solid was filtered off and washed the compound with Isopropyl alcohol (50ml). Dried the solid at 40-50°C to attain Racemic Dapoxetine oxalate 35-40 gm of the Purity by HPLC - 99.86%, S.O.R.-±0.5°

Example 9
Process for the preparation of (+)-N,N-dimethyl-l-phenyl-3-(l-
naphthalenyloxy)propanamine D (-)tartaric acid salt.(S-Dapoxetine Tartarate) which is from Recovered Racemic Dapoxetine

100 gm of the Recovered N, N-dimethyl-l-phenyl-3-(l-naphthalenyloxy) propanamine oxalate (Racemic Dapoxetine Oxalate) was suspended in mixture of methylene dichloride and water in a round bottom flask. Ammonia was added to attain pH 8.0-9.0. The layers were separated. The separated aqueous layer was extracted with methylenedichloride.The organic layers were washed with water (200ml). The solvent was evaporated under reduced pressure to obtain oil which was dissolved in Isopropyl alcohol(600) at 40-45°c followed by the addition of 17 gm of D(-) Tartaric acid in water(60ml). The reaction mass was maintained for 2-3 hrs at 40-45°c. The mixture further cooled to 25-30°C and maintained for 3-5hrs at the same temperature. Filtered the solid and washed the compound and dried to attain 35-40gm of the title compound having above 99.0% of chiral purity.

We Claims,

1. A process for recovering the Racemic Dapoxetine acid addition salt from the mother
liquor enriched with acid salt of R (-) Dapoxetine comprising steps of;

i. collecting the mother liquor enriched with tartaric acid salt of R (-) Dapoxetine with small amount of tartaric acid salt of S (+) Dapoxetine;

ii. Concentrating the liquid phase of step-i followed by treatment with base to obtain free Racemic Dapoxetine;

iii. Extracting the Racemic Dapoxetine of step (ii) in suitable organic solvent;

iv. Concentrating the extracted phase and isolating/recovering the crystalline Racemic Dapoxetine as acid addition salt by treatment with suitable acid in presence of suitable solvent to obtain Racemic Dapoxetine acid addition salt containing 1:1 mixture of R and S Dapoxetine acid addition salt.

2. A process for recovering the (S)- Dapoxetine from the mother liquor enriched with
acid salt of R (-) Dapoxetine comprising steps of;

i. collecting the mother liquor enriched with tartaric acid salt of R (-) Dapoxetine with small amount of tartaric salt of S (+) Dapoxetine;

ii. concentrating the liquid phase of (step-i) followed by treatment with base to obtain free Racemic Dapoxetine;

iii. extracting the Racemic Dapoxetine of step (ii) in suitable organic solvent;

iv. concentrating the extracted phase and isolating/recovering the crystalline racemic Dapoxetine as acid addition salt by treatment with suitable acid in presence of suitable solvent to obtain Racemic Dapoxetine acid addition salt containing 1:1 mixture of R and S Dapoxetine acid addition salt and

v. Resolving recovered racemic Dapoxetine (step iv) with optically pure acid like D (-) Tartaric acid or L (+) Tartaric acid in suitable solvent to obtain acid salt of enriched S (+) Dapoxetine in optically pure form followed by converting into optically pure S (+) Dapoxetine and its acid addition salts in pure form.

3. The process according to claims 1 or 2, wherein the base in step (ii) is selected from an inorganic base comprises sodium hydroxide, potassium hydroxide, sodium carbonate; ammonia and an organic base comprise triethylamine.

4. The process according to claim 3. where the base is selected from sodium Hydroxide, potassium Hydroxide.

5. The process according to claims 1 or 2, wherein the organic solvent used in step (iii) is selected from the group consisting of dichloromethane, ethylacetate.

6. The process according to claims 1 or 2, wherein the organic solvent used in step (iv) is selected from group consisting of C1-C4 alcohols such as methanol, ethanol, isopropyl alcohol and butyl alcohol; lower esters like Ethyl acetate, acetonitrile; acetone.

7. The process according to claims 1 or 2, wherein the acid is oxalic acid.

8. The process according to claim 2, wherein the suitable solvent used for resolution is
methylene dichloride.

9. A process for preparation of Racemic Dapoxetine of formula (II) and its acid addition salt, which comprises:

i) Condensing 3-chlorol-phenyl-propan-l-ol (Formula-Ill) with a-Naphthol with a suitable base in presence of phase transfer catalyst in water to give compound (Formula-IV),

ii) Reacting compound of (Formula-IV) with methane sulphonyl chloride in presence of base in suitable organic solvent followed by treatment with aqueous Dimethyl amine in presence of phase transfer catalyst to produce Racemic Dapoxetine base (Formula-II) and

iii) Treating Racemic Dapoxetine (Formula-II) with organic acid to obtain its acid addition salt in suitable solvent.

10. The process according to claim 9, where the solvent is used in step (ii) is selected from chlorinated solvents like Dichloro methane.

11. The process according to claim 9, where the Phase transfer catalyst is used in step (i) is Tetra butyl ammonium bromide.

12. The process according to claim 9, where the Phase transfer catalyst is used in step

(ii) is Tetra butyl ammonium bromide

13. The process according to claim 9, where the acid used in step (iii) is Oxalic acid.

14. The process according to claim 9, where the suitable solvent used in step (iii) is selected from group consisting of C1-C4 alcohols such as methanol, ethanol, isopropyl alcohol and butyl alcohol; lower esters like Ethyl acetate, acetonitrile or acetone.

15. A process for continuous preparation of (S)-Dapoxetine and its pharmaceutically acceptable acid addition salts in high yield and purity comprising;

i) Resolving Racemic Dapoxetine of Formula II with optically active acid in presence of suitable solvent to obtain acid salt of enriched S (+) Dapoxetine;

ii) Converting enanatiomerically pure salt of enriched S(+) Dapoxetine from (step-i)
into optically pure S(+)Dapoxetine by treating with base in presence of water and
water immiscible solvent; iii) Converting S (+)Dapoxetine into pharmaceutically acceptable acid addition salts in suitable solvent; iv) Recovering the Racemic Dapoxetine from mother liquor enriched with R and small amounts of S-Dapoxetine acid salts by treatment with a base in suitable solvent and vi) resolving Racemic Dapoxetine of Formula II with optically active acid in presence of suitable solvent to obtain acid salt of enriched S (+) Dapoxetine.

16. The process according to claim 15, wherein the optically active acid is selected from D (-) tartaric aced or L (+) Tartaric acid.

17. The process according to claim 15, wherein, the solvent used in step (i) is Aqueous Acetonitrile.

18. The process according to claim 15, wherein, the solvent used in step (i) is Aqueous Isopropyl alcohol.

19. The process according to claims 17 or 18, wherein the water content present in aqueous acetonitrile or aqueous isopropanol is 5-15%.

20. The process according to claim 15, wherein, optically active acid is D (-) tartaric acid, L (+) Tartaric acid used in sub molar quantities 0.40-0.90.

21. The process according to claim 15, wherein the water immiscible solvent used in step (ii) is selected from lower aromatic hydrocarbons, chlorinated hydrocarbons, lower esters.

22. The process according to claim 15, wherein the base used in step (ii) is selected from inorganic base comprises sodium hydroxide, potassium Hydroxide, sodium carbonate; ammonia or an organic base comprise triethylamine.

23. The process according to claim 15, wherein the acid addition salt is S (+) Dapoxetine oxalate or Dapoxetine Hydrochloride.

24. The process according to claim 15, where the suitable solvent used in step (iii) is selected from group consisting of C1-C4 alcohols such as methanol, ethanol, isopropyl alcohol and butyl alcohol; lower esters like Ethyl acetate; acetonitrile or acetone.