Field of the Invention

The present invention relates to an improved process for the preparation of (S)-N, N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine hydrochloride represented by the structural formula.

Formula-A

Background of the Invention

(S)-N, N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine is commonly known as Dapoxetine. Dapoxetine (INN, brand name Priligy) is a short-acting selective serotonin reuptake inhibitor (SSRI) marketed for the treatment of premature ejaculation in men. Dapoxetine is the only drug with regulatory approval for such an indication.

During the past decade, the relationship between monoamine uptake and a variety of
diseases and conditions has been appreciated and investigated. For example, the hydrochloride salt of fluoxetine ((dl-N-methyl-3-phenyl-3-[4-(trifiuoromethyl) phenoxy] propanamine)) is a selective serotonin (5-hydroxytryptamine) uptake inhibitor which has been approved by the Food and Drug Administration (FDA) for the treatment of depression and is also presently undergoing clinical evaluation for the treatment of eating disorders, alcoholism, and other disorders.

Similarly, tomoxetine hydrochloride (-)-N-methyl-3-phenyl-3-(2-methyl-
phenoxy)hydrochloride) is a selective inhibitor of norepinephrine uptake that is being investigated clinically for its antidepressant activity.

These compounds are among many taught in U.S. Pat. Nos. 4,018,895, 4,194,009, and 4,314,081 as being potent blockers of the uptake of various physiologically active monoamines including serotonin, norepinephrine and dopamine. U.S. Pat. No. 4,207,343 discloses 1-phenyl-3(substitutedphenoxy) propanamines as having the ability to block the uptake of a variety of monoamines.

More recently, U.S. Pat. No. 5,135,947 discloses l-phenyl-3-naphthalenyl oxy propanamines and their use as selective serotonin receptive inhibitors. The previously available synthetic route to l-phenyl-3-naphthalenyloxypropanamines, however, requires a chemical resolution to arrive at the chiral center.

However the aforesaid processes involve more number of steps and provide compounds with less yield and purity. Moreover, the said process involves the chromatographic purification techniques to get the pure compound, which is not recommended for the commercial scale process.

Hence there is a need in the art to develop an improved process for the preparation of Dapoxetine and its salts which alleviate the problems associated with prior art processes as referred above.

Advantages of Present Invention:

• Decreases the number of steps
• Provides a novel process for the preparation of racemic Dapoxetine oxalate salt
• Provides a novel process for the preparation of Dapoxetine hydrochloride salt
• Provides a novel polymorph of racemic Dapoxetine oxalate salt
• Provides a novel polymorph of Dapoxetine hydrochloride
• Improves the purity and yield of the final product
• Usage of gaseous HC1 to improve the purity of the product
• Eco-friendly process
• Uses simple, milder reagents which are easier to handle and use in large scale.

Brief Description of Drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form-M of Dapoxetine HC1.

Figure-2: Illustrates the IR spectrum of crystalline form-M of Dapoxetine hydrochloride.

Figure-3: Illustrates the DSC thermogram of crystalline form-M of Dapoxetine
hydrochloride.

Figure-4: Illustrates the PXRD pattern of crystalline form-S of recemic Dapoxetine oxalate.

Brief description of Invention:

The object of the present invention is to provide an improved process for the preparation of Dapoxetine and its salts which overcomes the disadvantages of prior-art processes.

Further, the process involves the usage of commercially available starting materials, simple reagents and low cost solvents which not only reduces the cost and number of steps, but also increaeses the yield and purity of the product.

The first aspect of the present invention is to provide an improved process for the preparation of Dapoxetine hydrochloride compound of formula-A, comprises of following steps,

a) Reacting benzene with 3-chloropropanoyl chloride in presence of a suitable acid in a suitable solvent to provide 3-chloro-l-phenylpropan-l-one compound of formula-I,

b) reducing the compound of formula-I with a suitable reducing agent in a suitable solvent provides 3-chloro-l-phenylpropan-l-ol compound of formula-II,

c) condensation of compound of formula-II with 1-napthol in presence of a suitable base in a suitable solvent to provide the 3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of formula-III,

d) reacting the compound of formula-III in-situ with methane sulfonyl chloride in presence of a suitable base in a suitable solvent followed by treatment with dimethyl amine provides the N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine, which is further treating in-situ with oxalic acid in a suitable solvent, optionally purifying in a suitable solvent to provides oxalate salt of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine, optionally purifying the N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV with a suitable solvent provides pure compound of formula-IV,

e) treating the compound of formula-IV with a suitable base and further resolution with D-tartaric acid in a suitable solvent provides (S)-N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine tartarate compound of fomula-V,

f) further converting the compound of formula-V into its free base by treating it with a suitable base and further treating it with Hcl(gas) in a suitable solvent provides (S)-N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine hydrochloride, optionally purifying the obtained compound from a suitable solvent provide pure Dapoxetine hydrochloride compound of formula-A.

The second aspect of the present invention is to provide a one-pot process for the preparation of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV comprises,

a) Condensation of compound of formula-II with 1-napthol in presence of a suitable base in a suitable solvent to provide the 3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of formula-III,

b) reacting the compound of formula-III in-situ with methyl sulphonyl chloride in presence of a suitable base in a suitable solvent followed by treating it with dimethyl amine provides the N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine, which is further reacting in-situ with oxalic acid in a suitable solvent provides N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine oxalate salt, optionally purifying it with a suitable solvent provides the compound of formula-IV.

The third aspect of the present invention is to provide a novel crystalline form of Dapoxetine hydrochloride compound of formula-A (herein designated as crystalline form-M) and also its process of preparation.

The fourth aspect of the present invention is to provide a novel crystalline form of racemic Dapoxetine oxalate compound of formula-IV (herein designated as crystalline form-S) and also process for its preparation.

The fifth aspect of the present invention is to provide a novel process for the preparation of (S)-N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l -amine tartarate compound of formula-V, comprises of treating the N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV with a suitable base, followed by in-situ resolution with a suitable chiral acid in a suitable solvent provides the compound of formula-V.

Detailed description of Invention:

As used herein the present invention, the term "suitable solvent" refers to the solvent
selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like; "hydrocarbon solvents" refers to toluene, xylene, cyclohexane, hexane, heptane and the like; "polar aprotic solvents" refers to dimethylsulfoxide, dimethylacetamide, dimethyl formamide, tetrahydrofuran, acetonitrile and the like; "polar protic solvents" refers to water , formic acid and aceticacid and the like; "chloro solvents" such as dichloro methane, dichloro ethane, carbon tetra chloride, and the like; "ketone solvents" such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, methyl tert-butyl ketone, methyl isopropyl ketone, diisopropyl ketone and the like; "esters solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; "polar aprotic solvents" such as dimethylsulfoxide, dimethyl acetamide, N-methyl pyrrolidinone, dimethyl formamide, propylene carbonate and the like; "ether solvents" refers to Diethylether, Diisopropylether and the like.
As used herein the present invention, the suitable base is an inorganic base selected from hydroxides, carbonates, bicarbonates and alkoxides of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonates, calcium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide and the like; or an organic base selected from dimethyl amine and tertiary amines such as triethyl amine, diisopropyl ethyl amine, tetramethyl ethylenediamine, tributyl amine, N-methyl morpholine, tetramethyl urea, N-methyl pyrrolidinone, pyridine, 4-dimethylamino pyridine, dimethyl aniline and the like.

As used herein, the term "Lewi's acid" refers to AICI3, SnCU and FeCl3 and the like; and "organic acids" refers to oxalic acid, maleic acid, malic acid, fumaric acid, succinic acid and the like; and "inorganic acids" refers to hydrochloric acid, sulfuric acid and the like; and "reducing agents" refers to Pd/C, NaBH*, LAH and Fe/HCl and the like;

As used herein the term "acid" used to form the acid addition salts of Dapoxetine is selected from the group comprising of oxalic acid, succinic acid, fumaric acid, malonic acid, malic acid, maleic acid, d-tartaric acid, 1-tartaric acid, dl-tartaric acid, citric acid, methanesulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid, phosphoric acid or hydrobromic acid and hydrochloric acid.

As used herein the term "chiral acid" refers to acid selected from S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (lR)-(-)-camphor sulfonic acid, (lS)-(+)-camphor sulfonic acid, (lR)-(+)-bromocamphor-10-sulfonic acid, (lS)-(-)-bromocamphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L-tataricacid, L(-)-pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine, D-lysine and mixtures thereof.

The first aspect of the present invention is to provide an improved process for the preparation of Dapoxetine hydrochloride compound of formula-A, comprises of following steps,

a) Reacting benzene with 3-chloropropanoyl chloride in presence of a suitable acid in a suitable solvent to provide 3-chloro-l-phenylpropan-l-one compound of formula-I,
Wherein, the suitable acid is Lewis acid selected from AICI3, SnCU and FeC^ and the suitable solvent is chloro solvent selected from dichloro methane, dichloro ethane and carbon tetra chloride,

b) reducing the compound of formula-I with a suitable reducing agent in a suitable solvent provides 3-chloro-1-phenylpropan-l-ol compound of formula-II,

Wherein, the suitable reducing agent is selected from NaBH4, UAIH4 and Fe/HCl, and the suitable solvent is selected from alcohol solvents, ether solvents, ketone solvents,

c) condensation of compound of formula-II with 1-napthol in presence of a suitable base in a suitable solvent to provide the 3-(naphthalen-1-yloxy)-1-phenylpropan-l-ol compound of formula-Ill,

Wherein, the suitable base is inorganic base selected from carbonates of alkali and alkaline earth metals such as sodium carbonate, calcium carbonate, potassium carbonate; and the suitable solvent is polar aprotic solvents, hydrocarbon solvents, ether solvents, ester solvents and alcohol solvents,

d) reacting the compound of formula-Ill in-situ with methane sulfonyl chloride in presence of a suitable base in a suitable solvent followed by treatment with dimethyl amine provides the N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine, which is further in-situtreating with oxalic acid in a suitable solvent provides N,N-dimethyl-3-(naphthalen-l-yloxy)-1-phenylpropan-l -amine oxalate salt, optionally purifying it with a suitable solvent provides pure N,N-dimethyl-3-(naphthalen-l-yloxy)- 1-phenylpropan-l -amine oxalate compound of formula-IV,

Wherein, the suitable base is organic base selected from triethyl amine, dimethyl amino pyridine (DMAP), N-methyl pyrrolidinone and diethyl aniline, diisopropyl ethylamine and pyridine, and a suitable solvent is selected from ester solvents, ether solvents, keto solvents, hydrocarbon solvents, chloro solvents and alcohol solvents.

e) treating the compound of formula-IV with a suitable base, and further in-situ resolution with D-tartaric acid in a suitable solvent to provide N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine tartarate compound of formula-V,

Wherein, the suitable base is selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates, and the suitable solvent is an ester solvents, ether solvents, keto solvents, alcohol solvents and mixture thereof,

f) further converting the compound of formula-V into its free base by treating it with a suitable base in a suitable solvent followed by treating it with hydrochloric acid (gas) in a suitable solvent provides Dapoxetine hydrochloride salt, optionally purifying it with a suitable solvent to provide the pure Dapoxetine hydrochloride salt compound of formula-A.

Wherein, the suitable base is selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates, and suitable solvent is selected from ester solvents, ether solvents, alcohol solvents and mixtures thereof.

In a preferred embodiment, an improved process for the preparation of Dapoxetine hydrochloride compound of formula-A, comprises of following steps,

a) Reacting benzene with 3-chloropropanoyl chloride in presence of a AICI3 in dichloromethane provides 3 -chloro-1 -phenylpropan-1 -one compound of formula-I,

b) reducing the compound of formula-I with sodium borohydride in methanol provides 3-chloro-1-phenylpropan-l-ol compound of formula-II,

c) condensation of compound of formula-II with 1-napthol in presence of potassium carbonate in dimethyl formamide provides the 3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of formula-III,

d) reacting the compound of formula-Ill in-situ with methane sulfonyl chloride in presence of triethyl amine, dimethylamino pyridine (DMAP) followed by treatment with dimethyl amine provides the N,N-dimethyl-3- (naphthalen-l-yloxy)-l-phenylpropan-l-amine, which is further in-situ treating with oxalic acid provides the N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV,

e) treating the compound of formula-IV with sodium hydroxide and further in-situ resolution with D-Tartaric acid provides (S)-N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine tartarate compound of formula-V,

f) further converting the compound of formula-V into its free base by treating it with sodium hydroxide and further treating it with hydrochloric acid (gas) in ethylacetate provides the Dapoxetine hydrochloride salt compound of formula-A.

The second aspect of the present invention is to provide a one-pot process for the preparation of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV comprises,

a) Condensation of 3-chloro-l-phenylpropan-l-ol compound of formula-II with 1-napthol in a suitable base in a suitable solvent to provides the 3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of formula-III,

Wherein, the suitable base is inorganic base selected from carbonates or bicarbonates of alkali and alkaline earth metals; and the suitable solvent is polar aprotic solvents hydrocarbon solvents, ester solvents, ether solvents, alcohol solvents and mixtures thereof,

b) reacting the compound of formula-Ill in-situ with methyl sulphonyl chloride in presence of a suitable base in a suitable solvent followed by treatment with dimethyl amine provides the N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine, which is further in-situtreating with oxalic acid in a suitable solvent provides the N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV,

Wherein, the suitable base is organic base selected from dimethyl amine, triethyl amine, dimethylamino pyridine (DMAP), N-methyl pyrrolidinone and dimethyl aniline, diisopropyl ethylamine, and a suitable solvent is selected from ester solvents, ether solvents, keto solvents, hydrocarbon solvents, chloro solvents and alcohol solvents.

In a preferred embodiment, the one-pot process for the preparation of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV, comprises of condensation of 3-chloro-l-phenylpropan-l-ol compound of formula-II with 1-napthol in the presence of potassium carbonate in dimethyl formamide provides 3-(naphthalen-l-yloxy)-l-phenylpropan-1-ol compound of formula-Ill, which in-situ reacts with methyl sulphonyl chloride in presence of triethyl amine and dimethylamino pyridine (DMAP) followed by reaction with dimethyl amine provides the N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine, which is further in-situ reacts with oxalic acid provides the N,N-dimethyl-3-(naphthalen-l-yloxy)-1 -phenylpropan-1 -amine oxalate compound of formula-IV.

The obtained compound of formula-IV is converted into pure racemic Dapoxetine compound of formula-VI by treating it with a suitable base in a suitable solvent. Further, the obtained pure compound of formula-VI can be converted into pure Dapoxetine hydrochloride compound of formula-A by the prior known methods.

The present invention avoids the chromatographic purification techniques in the preparation of racemic Dapoxetine, which are expensive and not recommended for the commercial process.

The third aspect of the present invention is to provide a novel crystalline form of Dapoxetine hydrochloride, herein designated as form-M. Further, the crystalline form-M of Dapoxetine hydrochloride in accordance with the present invention is characterized by its powder XRD pattern having peaks at about 8.8, 14.3, 15.0, 16.3, 16.6, 17.8, 18.8, 19.1, 20.6, 22.7, 23.8, 25.2, 29.0 and 29.5 ± 0.2 degrees two-theta and substantially as shown in figure-1; its IR spectrum having peaks at about 1076, 1241 and 1272 cm"1 and substantially as shown in figure-2; by its DSC thermogram showing endotherm at about 183.27°C as shown in figure-3.

The fourth aspect of the present invention is to provide a novel crystalline form of racemic Dapoxetine oxalate, herein designated as crystalline form-S. Further, the crystalline form-S of racemic Dapoxetine oxalate in accordance with the present invention is characterized by its powder XRD pattern having peaks at about 4.3, 8.5, 10.6, 12.6, 12.8, 20.0, 21.3, 22.4, 24.1, 26.4 and 28.1 ± 0.2 degrees two-theta and substantially as shown in figure-4.

The obtained crystalline form-S of racemic Dapoxetine oxalate compound of formula-IV is used to prepare the pure racemic Dapoxetine compound of formula-VI as well as pure Dapoxetine hydrochloride compound of formula-A.

The fifth aspect of the present invention is to provide a novel process for the preparation of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine tartarate compound of formula-V, comprises of treating N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV with a suitable base and further in-situ resolution it with D-tartaric acid in a suitable solvent provides the compound of formula-V.

Wherein, the suitable base is hydroxides of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide etc.

In a preferred embodiment, a novel process for the preparation of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine tartrate compound of fomula-V, comprises of treating N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV with sodium hydroxide and further in-situ resolution it with D- Tartaric acid in ethyl acetate provides the compound of formula-V.

The present invention is represented schematically as follows:

Dapoxetine Hydrochloride

The process described in the present invention was demonstrated in examples as illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention:

Examples:

Example-1: Preparation of 3-chIoro-l-phenylpropan-l-one (Formula-I)

3-chloropropanoyl chloride (71.4 g) was added to a solution of aluminium chloride (82.85 g) in dichloromethane (300 ml) under nitrogen at 0-5°C and stirred for 30 minutes at the same temperature. A mixture of benzene (50 g) and dichloromethane (50 ml) was added to the reaction mixture at 0-5°C over a period of 2 hours and then stirred for 1 hour at 0-10°C. The temperature of reaction mixture was raised to 10-20°C and then stirred for 2 hours at 10-20°C. After completion of the reaction, the reaction mixture was poured into a mixture of crushed ice and hydrochloric acid at < 5°C and then stirred for 30 minutes at 5-10°C. The temperature of reaction mixture was raised to 25-30°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane combined both the organic layers and washed with water followed by 10% sodium bicarbonate solution and finally with water. Distilled off the solvent from organic layer completely and co-distilled with pet ether to get the residue. Pet ether (100 ml) was added to the obtained residue and heated the reaction mixture to reflux temperature. Stirred the reaction mixture for 20 minutes at reflux temperature and the reaction mixture was cooled to 25-30°C, further to 0-5°C and then stirred for 1 hour at 0-5°C. Filtered the obtained solid, washed with pet ether and dried to get the title compound. Yield: 80 grams; MR: 36-42°C

Example-2: Preparation of 3-chloro-l-phenylpropan-l-ol (Formula-II)

Sodium borohydride (7 g) was added to a solution of 3-chloro-l-phenylpropan-l-one compound of formula-I (50 g) in methanol (250 g) at 0-5°C and then stirred for 30 minutes at 0-5°C. After completion of the reaction, pH of the reaction mixture was adjusted to 5.3 with acetic acid at 0-5°C. Distilled off the solvent from the reaction mixture completely under reduced pressure. Dichloromethane and water was added to the obtained residue at 25-30°C and stirred the reaction mixture for 10 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted twice with dichloromethane. The organic layers were combined, washed with 10% sodium bicarbonate followed by water and then distilled off the solvent under reduced pressure to get the title compound. Yield: 50 grams

Example-3: Preparation of 3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol (Formula-Ill)

A mixture of 3-chloro-l-phenylpropan-l-ol compound of formula-II (50 g), 1-naphthol (36.5 g), potassium carbonate (46.5 g) and dimethylsulfoxide (250 g) was heated to 85-90°C and then stirred for 4 hours at 85-90°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C and poured it into crushed ice. The temperature of the reaction mixture was raised to 20-30°C. The reaction mixture was extracted twice with toluene. The organic layers were combined, washed with 5% sodium hydroxide solution followed by water and then distilled off the solvent to get the residue. The obtained residue was cooled to 40-45°C. Pet. Ether (200 ml) was added to the residue at 40-45°C, heated to reflux temperature and stirred for 30 minutes at reflux temperature. The reaction mixture was cooled to 20-25°C, further cooled to 0-5°C and then stirred for 1 hour at 0-5°C. Filtered the solid, washed with pet.ether and then dried to get the compound. Yield: 75 grams; MR: 32-36°C

Example-4: Preparation of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate salt (Formula-IV)

A solution of methane sulfonyl chloride (30.5 g) in tetrahydrofuran (95 ml) was added to a mixture of 3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of formula-Ill (50 g), triethyl amine (36.4 g), dimethyl amino pyridine (0.0025 g) and tetrahydrofuran (360 ml) at 0-5°C and then stirred for 6 hours at 0-5°C. After completion of the reaction, dimethyl amine (80 g) gas was passed slowly into the reaction mixture at 0-5 °C, raised the temperature of the reaction mixture to 25-30°C and then stirred for 40 hours at 25-30°C.

After completion of the reaction, the reaction mixture was poured into crushed ice and pH of the reaction mixture was adjusted to 0.7 with hydrochloric acid at 0-5°C. Toluene was added to the reaction mixture and the temperature was raised to 20-3 0°C. Both the organic and aqueous layers were separated; p of the aqueous layer was adjusted to 8.5 with 50% sodium hydroxide solution at 20-30°C. The reaction mixture was extracted twice with dichloromediane. The dichloromethane layers were combined, distilled off the solvent completely under reduced pressure and co-distilled with ethylacetate. The obtained residue was cooled to 25-3 0°C and added ethyl acetate (200 ml) followed by oxalic acid (15.5 g). The reaction mixture was heated to reflux temperature and then stirred for 30 minutes at reflux temperature. The reaction mixture was cooled to 25-30°C and then stirred for 30 minutes at 25-30°C. Filtered the solid, washed with ethylacetate and then dried to get the title compound. Yield: 55 grams; MR: 88-94°C

The PXRD of the obtained racemic Dapoxetine oxalate salt compound of formula-IV (herein referred as crystalline form-S) is depicted in figure-4.

ExampIe-5: Preparation of (S)-N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenyl propan-1-amine D- tartarate salt (Formula-V)

A mixture of N,N-dimethyl-3-(naphmalen-l-yloxy)-l-phenylpropan-l-amine oxalate salt compound of formula-IV (50 g), dichloromethane (250 ml) and water (100 ml) was cooled to 10-15°C. PH of the reaction mixture was adjusted to 10.3 with 10% sodium hydroxide solution at 10-15°C and then stirred for 10 minutes at 10-15°C. Filtered the reaction mixture and washed with dichloromethane. Both the organic and aqueous layers were separated from the filtrate and the aqueous layer was extracted with dichloromethane. Both the organic layers were combined and washed with water.

Distilled off the solvent completely and co-distilled with ethyl acetate to get the residue.

The obtained residue was cooled to 25-30°C. Ethyl acetate (150 ml), water (1000 ml) followed by D(-)-tartaric acid (19 g) were added to the reaction mixture at 25-30°C and then stirred for 30 minutes at 25-30°C. The reaction mixture was heated to 60-65°C and then stirred for 30 minutes at 60-65°C. Cooled the reaction mixture to 25-30°C and then stirred for 30 minutes at 25-30°C. Filtered the solid, washed with water and then dried to get the solid. Yield: 22 grams

Example-6: Preparation of (S)-N,N-dimethyl-3-(naphthalen-l-yloxy)-l-pheiiyl propan-1-amine hydrochloride salt (Formula-A)

Water (100 ml) was added to a solution of (S)-N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine D- tartarate compound of formula-V (50 g) in dichloromethane (250 ml) and cooled to 10-15°C. PH of the reaction mixture was adjusted to 10.3 with 10% sodium hydroxide solution at 10-15°C and then stirred for 10 minutes at 10-15°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both the organic layers were combined and washed with water. Distilled off the solvent completely and co-distilled with ethyl acetate to get the residue.

The obtained residue was cooled to 25-30°C. Ethyl acetate (150 ml) and carbon (5 g) were added to the obtained residue and then stirred for 20 minutes at 25-30°C. Filtered the reaction mixture, washed with ethyl acetate and the obtained filtrate was cooled to 0-5°C. PH of the reaction mixture was adjusted to 2.3 bypassing hydrochloric acid gas into the reaction mixture at 0-5°C and stirred for 30 minutes. Filtered the solid, washed with ethyl acetate and then dried to get the title compound.

Yield: 30 grams

Example-7: One pot process for the preparation of N,N-dimethyI-3-(naphthalen-l-yloxy)-1-phenylpropan-l-amine oxalate salt (Formula-IV)

A mixture of 3-chloro-l-phenylpropan-l-ol compound of formula-II (50 g), 1-naphthol (36.5 g), potassium carbonate (46.5 g) and dimethylformamide (75 ml) was heated to 85-90°C and then stirred for 4 hours at 85-90°C. After completion of the reaction, the reaction mixture was cooled 25-30°C and then quenched by pouring the reaction mixture into crushed ice. The temperature of reaction mixture was raised to 20-30°C and the compound was extracted twice with toluene. The toluene layers were combined, washed with 5% sodium hydroxide solution followed by water and then dried with sodium sulphate. Triethyl amine (94.64 g) followed by dimethyl amino pyridine (0.0065 g) were added to the obtained organic layer and cooled to 0-5°C. Methane sulfonyl chloride (79.3 g) was slowly added to the reaction mixture at 0-5°C and then stirred for 6 hours at 0-5°C. After completion of the reaction, dimethyl amine gas (80 g) was passed into the reaction mixture at 0-5°C, the temperature of the reaction mixture was raised to 25-30°C and then stirred for 40 hours at 25-30°C. After completion of the reaction, the reaction mixture was quenched into crushed ice and pH of the reaction mixture was adjusted to 0.7 with hydrochloric acid. The temperature of reaction mixture was raised to 20-30°C and both the organic and aqueous layers were separated. PH of the obtained aqueous layer was adjusted to 8.5 with 50% sodium hydroxide at 20-30°C and the reaction mixture was extracted twice with dichloromethane. The dichloromethane layers were combined, distilled off the solvent completely under reduced pressure and co-distilled with ethylacetate. The obtained residue was cooled to 25-30°C and added ethyl acetate (300 ml) followed by oxalic acid (22.8 g). The reaction mixture was heated to reflux temperature and then stirred for 30 minutes at reflux temperature. The reaction mixture was cooled to 25-30°C and then stirred for 30 minutes at 25-30°C. Filtered the solid, washed with ethylacetate and then dried to get the title compound.

Yield: 72 grams

Example-8: One pot process for the preparation of N,N-dimethyl-3-(naphthalen-l-yloxy)-1-phenylpropan-l-amine oxalate salt (Formula-IV)

A mixture of 3-chloro-l-phenylpropan-l-ol compound of formula-II (50 g), 1-naphthol (36.5 g), potassium carbonate (46.5 g) and dimethyl sulfoxide (250 g) was heated to 85-90°C and then stirred for 4 hours at 85-90°C. After completion of the reaction, the reaction mixture was cooled 25-30°C and then quenched by pouring the reaction mixture into crushed ice. The temperature of reaction mixture was raised to 20-3 0°C and the compound was extracted twice with toluene. The toluene layers were combined, washed with 5% sodium hydroxide solution followed by water and then dried with sodium sulphite. Triethyl amine (94.64 g) followed by dimethyl amino pyridine (0.0065 g) were added to the obtained organic layer and cooled to 0-5°C. Methane sulfonyl chloride (79.3 g) was slowly added to the reaction mixture at 0-5°C and then stirred for 6 hours at 0-5°C. After completion of the reaction, dimethyl amine gas (80 g) was passed into the reaction mixture, the temperature of the reaction mixture was raised to 25-30°C and then stirred for 40 hours at 25-30°C. After completion of the reaction, the reaction mixture was quenched with crushed ice and pH of the reaction mixture was adjusted to 0.7 with hydrochloric acid at 0-5°C. The temperature of reaction mixture was raised to 20-30°C and both the organic and aqueous layers were separated. PH of the obtained aqueous layer was adjusted to 8.5 with 50% sodium hydroxide and the reaction mixture was extracted twice with dichloromethane. The dichloromethane layers were combined, distilled off the solvent completely and co-distilled with ethylacetate. The obtained residue was cooled to 25-30°C and added ethyl acetate (300 ml) followed by oxalic acid (22.8 g). The reaction mixture was heated to reflux temperature and then stirred for 30 minutes at reflux temperature. The reaction mixture was cooled to 25-30°C and then stirred for 30 minutes at 25-30°C. Filtered the solid, washed with ethylacetate and then dried to get the title compound. Yield: 73 grams Example-9: Preparation of pure N,N-dimethyl-3-(naphthaIenel-yloxy)-l-phenyl propan-1-amine (Formula-VI) (pure racemic Dapoxetine)

A mixture of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate salt compound of formula-IV (100 g), dichloromethane (500 ml) and water (200 ml) was cooled to 10-15°C. PH of the reaction mixture was adjusted to 10.3 with 10% sodium hydroxide solution at 10-15°C and then stirred for 10 minutes at 10-15°C. Filtered the reaction mixture and washed with dichloromethane. Both the organic and aqueous layers were separated from the filtrate and the aqueous layer was extracted with dichloromethane. Both the organic layers were combined and washed with water. Distilled off the solvent completely and co-distilled with ethyl acetate to get the pure title compound. Yield: 70 grams

Example-10: Preparation of (S)-N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenyl propan-1-amine D- tartarate salt (Formula-V)

To the pure compound of formula-VI (70 grams) obtained from the example-9 added ethyl acetate (300 ml), water (2000 ml) followed by D(-)-tartaric acid (38 g) were added to the reaction mixture at 25-30°C and then stirred for 30 minutes at 25-30°C. The reaction mixture was heated to 60-65°C and then stirred for 30 minutes at 60-65°C. Cooled the reaction mixture to 25-30°C and then stirred for 30 minutes at 25-30°C. Filtered the solid, washed with water and then dried to get the solid. Yield: 45 grams

Example-11: Preparation of 3-chloro-l-phenylpropan-l-ol (Formula-II)

Sodium borohydride (5 g) was added to a solution of 3-chloro-l-phenylpropan-l-one compound of formula-I (50 g) in dichloromethane (100 ml) at 0-5°C, followed by methanol (35 ml) over a period of 45 minutes at 0-5°C and then stirred for 1 hour at 0-5°C. After completion of the reaction, pH of the reaction mixture was adjusted to 5.3 with acetic acid at 0-5°C and temperature of the reaction mixture was raised to 20-25°C. Water was added to the reaction mixture and both the organic and aqueous layers were separated. The aqueous layer was extracted twice with dichloromethane. The dichloromethane layers were combined, washed with water and then dried with sodium sulphate and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 50 grams

Example-12: Preparation of 3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol (Formula-Ill)

A mixture of 3-chloro-l-phenylpropan-l-ol compound of formula-II (50 g), 1-naphthol (36.5 g), potassium carbonate (46.5 g), acetone (250 g) and dimethyl formamide (50 ml) was heated to 60-65°C and then stirred for 16 hours at 60-65°C. After completion of the reaction, distilled off the solvent completely from the reaction mixture and then cooled to 25-30°C. The reaction mixture was quenched by pouring the reaction mixture into crushed ice. The temperature of reaction mixture was raised to 20-30°C and then extracted twice with toluene. The toluene layers were combined and washed with 5% sodium hydroxide solution followed by water and distilled off the solvent under reduced pressure to get the residue. The obtained residue was cooled to 40-45°C and pet.ether (200 ml) was added to it at 40-45°C. The reaction mixture was heated to reflux temperature and then stirred for 30 minutes at the same temperature. The reaction mixture was cooled to 20-25°C, further cooled to 0-5°C and then stirred for 1 hour at 0-5°C. Filtered the solid, washed with pet.ether and then dried to get the title compound. Yield: 75 grams

Example-13: Preparation of 3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol (Formula-Ill)

A mixture of 3-chloro-l-phenylpropan-l-ol compound of formula-II (50 g), 1-naphthol (36.5 g), potassium carbonate (46.5 g) and dimethyl formamide (75 ml) was heated to 85-90°C and then stirred for 4 hours at 85-90°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C. The reaction mixture was quenched by pouring the reaction mixture into crushed ice. The temperature of reaction mixture was raised to 20-3 0°C and then extracted twice with toluene. The toluene layers were combined, washed with 5% sodium hydroxide solution followed by water and distilled off the solvent to get the residue. The residue obtained was cooled to 40-45°C and pet.ether (200 ml) was added to it. The reaction mixture was heated to reflux temperature and then stirred for 30 minutes at the same temperature. The reaction mixture was cooled to 20-25°C, further to 0-5°C and then stirred for 1 hour at 0-5°C. Filtered the solid, washed with petether and then dried to get the title compound. Yield: 65 grams

Example-14: Recovery process for the preparation of N,N-dimethyI-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine

A mixture of (R)-N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine (18 g) and LiHMDS (200 ml) was heated to 40-45°C and then stirred for 50 hours at 40-45°C. The reaction mixture was cooled to 25-30°C and then quenched into ice. PH of the reaction mixture was adjusted to 8.5 with hydrochloride and the compound was extracted twice with dichloromethane. The dichloromethane layers were combined, washed with water and then distilled to get the title compound. Yield: 15 grams

We Claim:

1. A Novel crystalline form-S of racemic Dapoxetine oxalate salt is characterized by, its powder XRD pattern having peaks at about 4.3, 8.5, 10.6, 12.6, 12.8, 20.0, 21.3, 22.4, 24.1, 26.4 and 28.1 ± 0.2 degrees two-theta and substantially as shown in figure-4.

2. One-pot process for the preparation of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine oxalate compound of formula-IV, comprising of:

a) Condensation of 3-chloro-l-phenylpropan-l-ol compound of formula-II with 1-napthol in a suitable base selected from carbonates or bicarbonates of alkali and alkaline earth metals in a suitable solvent selected from polar aprotic solvents, hydrocarbon solvents, ester solvents, ether solvents, alcohol solvents and mixtures thereof to provide the 3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of formula-Ill,

b) reacting the compound of formula-Ill in-situ with methylsulphonyl chloride in presence of a suitable base selected from dimethyl amine, triethyl amine, dimethylamino pyridine (DMAP), N-methyl pyrrolidinone and dimethyl aniline, diisopropyl ethylamine in a suitable solvent selected from ester solvents, ether solvents, keto solvents, hydrocarbon solvents, chloro solvents and alcohol solvents followed by treatment with dimethyl amine to provide N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine, which on in-situ treatment with oxalic acid in a suitable solvent to provide N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV.

3. One-pot process for the preparation of crystalline form-S of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV, comprising of, condensation of 3-chloro-l-phenylpropan-l-ol compound of formula-II with 1-napthol in the presence of potassium carbonate in dimethyl formamide to provide 3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of formula-Ill, which on in-situ treatment with methylsulphonyl chloride in presence of triethylamine and dimethylamino pyridine (DMAP) followed by reaction with dimethyl amine to provide N,N-dimethyl-3-(naphthalen-l-yloxy)-1-phenylpropan-l-amine, which on in-situ reacts with oxalic acid in ethylacetate to provide N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV.

4. A novel process for the preparation of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine tartarate compound of formula-V, comprising of, reacting N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV with a suitable base selected from hydroxides of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide followed by in-situ treatment with D-tartaric acid in a suitable solvent selected from ester solvent to provide compound of formula-V.

5. A novel process for the preparation of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine tartrate compound of formula-V, comprising of, treating N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV with sodium hydroxide followed by in-situ treatment with D-Tartaric acid in ethyl acetate to provide the compound of formula-V.

6. An improved process for the preparation of Dapoxetine hydrochloride compound of formula-A, comprising the following steps of:

a) Reacting benzene with 3-chloropropanoyl chloride in presence of a suitable acid in a suitable solvent to provide 3-chloro-l-phenylpropan-l-one compound of formula-I,
Formula-I

b) reducing the compound of formula-I with a suitable reducing agent in a suitable solvent to provide 3-chloro-l-phenylpropan-l-ol compound of formula-II,

Formula-II

c) condensation of compound of formula-II with 1-napthol in presence of a suitable base in a suitable solvent to provide the 3-(naphthalen-l-yloxy)-l-phenylpropan-
l-ol compound of formula-III,

Formula-III

d) reacting the compound of formula-Ill in-situ with methanesulfonyl chloride in presence of a suitable base in a suitable solvent followed by treatment with dimethyl amine to provide the N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenyl propan-1-amine, which on in-situ treatment with oxalic acid in a suitable solvent to provide crystalline form-S of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate salt, optionally purifying it with a suitable solvent to provide pure N,N-dimethyl-3-(naphthalen-l-yloxy)-1-phenylpropan-l -amine oxalate compound of formula-IV,

Formula-IV
e) reacting the compound of formula-IV with a suitable base followed by in-situ treatment with D-tartaric acid in a suitable solvent to provide N,N-dimethyl-3-(naphthalen-l- yloxy)-l-phenylpropan-l-amine tartarate compound of formula-V,

Formula-V f) further converting the compound of formula-V into its free base by treating it with a suitable base in a suitable solvent followed by treating it with hydrochloric acid in a suitable solvent to provide Dapoxetine hydrochloride salt, optionally purifying it with a suitable solvent to provide pure Dapoxetine hydrochloride salt compound of formula-A.

The process according to claim 6, wherein,

In step-a) the suitable acid is Lewis acid selected from AICI3, SnCl4 and FeCl3; and the suitable solvent is chloro solvent selected from dichloromethane, dichloro ethane and carbon tetra chloride,

In step-b) the suitable reducing agent is selected from NaBFL;, LiAlH4 and Fe/HCl; and the suitable solvent is selected from alcohol solvents, ether solvents and ketone solvents,

In step-c) the suitable base is inorganic base selected from carbonates of alkali and alkaline earth metals such as sodium carbonate, calcium carbonate, potassium carbonate; and the suitable solvent is polar aprotic solvents, hydrocarbon solvents, ether solvents, ester solvents and alcohol solvents,

In step-d) the suitable base is organic base selected from triethyl amine, dimethyl amino pyridine (DMAP), N-methyl pyrrolidinone and diethyl aniline, diisopropyl ethylamine and pyridine; and a suitable solvent is selected from ester solvents, ether solvents, keto solvents, hydrocarbon solvents, chloro solvents and alcohol solvents,

In step-e) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates; and the suitable solvent is selected from ester solvents, ether solvents, keto solvents, alcohol solvents and mixture thereof,

In step-f) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates; and suitable solvent is selected from ester solvents, ether solvents, alcohol solvents and mixtures thereof.

8. An improved process for the preparation of Dapoxetine hydrochloride compound of formula-A, comprising the following steps of:

a) Reacting the benzene with 3-chloropropanoyl chloride in presence of a AICI3 in dichloromethane to provide 3-chloro-1-phenylpropan-l-one compound of formula-I,

b) reducing the compound of formula-I with sodium borohydride in methanol to provide 3-chloro-1-phenylpropan-l-ol compound of formula-II,

c) condensation of compound of formula-II with 1-napthol in presence of potassium carbonate in dimethyl formamide to provide the 3-(naphthalen-l-yloxy)-l-phenylpropan-l-ol compound of formula-III,

d) reacting the compound of formula-Ill in-situ with methanesulfonyl chloride in presence of triethylamine, dimethylamino pyridine (DMAP) followed by treatment with dimethyl amine to provide the N,N-dimethyl-3-(naphthalene-l-yloxy)-l-phenylpropan-l-amine, which on in-situ treatment with oxalic acid in ethylacetate to provide crystalline form-S of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV,

e) reacting the compound of formula-IV with sodium hydroxide followed by in-situ treatment with D-Tartaric acid to provide (S)-N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-1-amine tartarate compound of formula-V,

f) further converting the compound of formula-V into its free base by treating it with sodium hydroxide and further treating it with hydrochloric acid in ethyl acetate to provide the Dapoxetine hydrochloride salt compound of formula-A.

9. A process for the preparation of N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate salt compound of formula-IV comprising of, reacting the N,N-dimethyl-3-(naphthalene-l-yloxy)-l-phenylpropan-l-amine free base with oxalic acid in ethylacetate to provide N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine oxalate compound of formula-IV.

10. A crystalline form of Dapoxetine hydrochloride compound of formula-A characterized by,

a) its powder XRD pattern having peaks at about 8.8, 14.3, 15.0, 16.3, 16.6, 17.8, 18.8, 19.1, 20.6, 22.7, 23.8, 25.2, 29.0 and 29.5 ± 0.2 degrees two-theta and substantially as shown in figure-1;

b) its IR spectrum having peaks at about 1076, 1241 and 1272 cm"1 and substantially as shown in figure-2;

c) its DSC thermogram showing endotherm at about 183.27°C as shown in figure-3.