INTRODUCTION

Aspects of the present application relate to processes for the preparation of dapoxetine hydrochloride.

The drug compound having the adopted name "dapoxetine hydrochloride" can be represented by structural formula (I) and belongs to the pharmacotherapeutic group of selective serotonin reuptake inhibitors (SSRIs).

Dapoxetine hydrochloride is a white to slightly yellow powder. A chemical name for dapoxetine hydrochloride is (+)-(S)-N,N-dimethyl-(a)-[2-(1-naphthalenyloxy)ethyl]-benzenemethanamine hydro chloride and it is the active ingredient in PRILIGY® tablets, sold for the treatment of premature ejaculation in men aged 18 to 64.

U.S. Patent No. 5,135,947 discloses 1-phenyl-3-napthalenyloxy-propanamines and their use as selective serotonin receptive inhibitors. A number of syntheses of dapoxetine hydrochloride have been reported in US 5,292,962, WO 2008/035358 A2, CN100591649C, CN 100402488C, CN1279018C.

However, there remains a need for an environmentally-friendly, cost-effective, and industrially applicable processes for the preparation of dapoxetine hydrochloride which alleviates the problems associated with the prior art processes as discussed above.

SUMMARY
One aspect of the application provides a process for the preparation of dapoxetine hydrochloride of Formula I, which comprises:
a) reducing 3-chloro-1-phenylpropan-1-one to provide (R)-3-chloro-1-phenylpropan-1-ol, compound of Formula II;

Formula II

b) reacting the compound of Formula II obtained in step a) with 1-naphthol to provide the compound of Formula III;

Formula III

c) reacting the compound of Formula III obtained in step b) with methanesulfonyl chloride to provide the compound of Formula IV;

Formula IV

d) reacting the compound of Formula IV obtained in step c) with dimethylamine to provide dapoxetine compound of Formula V; and

Formula V

e) converting dapoxetine obtained in step d) to dapoxetine hydrochloride in presence of a source of hydrogen chloride.

Another aspect of the application provides a process for the preparation of dapoxetine hydrochloride compound of Formula I, which comprises:

a) reacting methyl cinnamate with R-(+)-N-Benzyl-a-methylbenzylamine of Formula VI:

Formula VI to provide a compound of Formula VII;

Formula VII

b) debenzylating the compound of Formula VII obtained in step a) to provide a compound of Formula VIII;

Formula VIM

c) reducing the compound of Formula VIII obtained in step b) to provide a compound of Formula IX;

Formula IX

d) N-methylating the compound of Formula IX obtained in step c) to provide a compound of formula X;

Formula X
e) reacting the compound of Formula X obtained in step d) with 1-fluoronaphthalene to provide dapoxetine; and

f) converting dapoxetine obtained in step e) to dapoxetine hydrochloride in presence of a source of hydrogen chloride.

Another aspect of the application provides a process for the preparation of dapoxetine hydrochloride of Formula I, which comprises:

a) reducing D-phenylglycine followed by N-Boc protection or reducing N-Boc-D-phenylglycine to provide a compound of Formula XI;

Formula XI

b) reacting the compound of Formula XI obtained in step a) with methanesulfonyl chloride to provide a compound of Formula XII;

Formula XII

c) treating the compound of Formula XII obtained in step b) with sodium cyanide to provide a compound of Formula XIII;

d) hydrolyzing the compound of Formula XIII obtained in step c) to provide a compound of Formula XIV;

Formula XIV

e) reducing the compound of Formula XIV obtained in step d) to provide a compound of Formula XV;

Formula XV

f) deprotecting the compound of Formula XV obtained in step e) using acid to produce a compound of Formula IX;

Formula IX

g) N-methylating the compound of Formula IX obtained in step f) to produce a compound of Formula X;

h) reacting the compound of Formula X obtained in step g) with 1-
fluoronaphthalene to provide dapoxetine; and

i) converting dapoxetine obtained in step h) to dapoxetine hydrochloride in presence of a source of hydrogen chloride.

Another aspect of the application provides a process for the preparation of highly pure (+) dapoxetine or an acid addition salt thereof, which comprises:

a) resolving racemic dapoxetine with a chiral acid to obtain a chiral acid salt of (+)-dapoxetine;

b) converting the chiral acid salt of (+)-dapoxetine prepared in step (a) to (+)-dapoxetine; and

c) optionally converting the (+)-dapoxetine obtained in step b) into an acid addition salt.

DETAILED DESCRIPTION

One aspect of the application provides a process for the preparation of dapoxetine hydrochloride compound of Formula I, which comprises:

a) reducing 3-chloro-1-phenylpropan-1-one to provide (R)-3-chloro-1-phenylpropan-1-ol .compound of Formula II;

Formula II

b) reacting the compound of Formula II obtained in step a) with 1-naphthol to provide the compound of Formula III;

Formula III

c) reacting the compound of Formula III obtained in step b) with methanesulfonyl chloride to provide the compound of Formula IV;

Formula IV

d) reacting the compound of Formula IV obtained in step c) with dimethylamine to provide dapoxetine compound of Formula V; and

Formula V

e) converting dapoxetine obtained in step d) to dapoxetine hydrochloride in presence of a source of hydrogen chloride.

According to the aspect of the application the preparation of dapoxetine hydrochloride is as described in the scheme-1.

Scheme-1

Step a) involves the reduction of 3-chloro-1-phenylpropan-1-one to provide (R)-3-chloro-1 -phenylpropan-1 -ol.

In embodiments of step a), the reduction may be carried out by using a suitable reducing agent. The reduction may be carried out by using chiral reducing agents such as (+) Diisopinocampheylchloroborane [(+) DIP chloride], Borane with chiral oxazaborolidine as catalyst, and borane and 9-BBN with chiral α,α-diphenyl-2-pyrrolidine methanol as catalyst.

In embodiments of step a), the reaction may be carried out in a suitable inert solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of such solvents include ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, chlorobenzene or dichlorobenzene or their mixture thereof.

In embodiments of step a), the reaction can be carried out at a temperature ranging from about -10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about -5°C to room temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of about 1 to about 24 hours or longer.

In embodiments of step a), the product may be isolated directly from the reaction mixture itself after the reaction is complete, or after conventional work up with techniques such as quenching with a suitable reagent, extraction, or the like.

In embodiments of step a), the product of step-a), i.e., compound of Formula II is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation.

In embodiments of step a), the product of step-a), i.e., compound of Formula II may be used in the next step without isolation.

Step-b) involves the reaction of compound of Formula II with 1-naphthol to provide the compound of Formula III.

In embodiments of step b), the reaction can be carried out in the presence of a base. In embodiments, the reaction can also be carried out in the presence of aqueous base. Bases that are useful in the reaction include, but are not limited to: inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, or alkoxides, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, barium hydroxide, calcium oxide, or alkali metal hydrides e.g. sodium hydride, potassium hydride, or the like; or organic bases such as, for example, tertiary amines, e.g., triethylamine, N,N-dimethylethanolamine, N,N-diethylethanolamine, 4-ethylmorpholine, 1,4-diazabicyclo[2.2.2]-octane, N-methyl morpholine, dimethylaminopyridine, diisopropylamine, diisopropylethylamine, pyridine, or the like.

In embodiments of step b), the reaction can be carried out in the presence of a suitable inert solvent. The reaction can be carried out in an aprotic polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, or the like.

In embodiments of step b), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 5°C to 90°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.

In embodiments of step b), the product may be isolated directly from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as quenching with a suitable reagent, extraction or the like.

In embodiments of step b), the product of step-b), i.e., compound of Formula III is optionally isolated by extracting in a suitable solvent followed by removal of the solvent by evaporation. In embodiments of step b), the product of step-b), i.e., compound of Formula III may be used in the next step without isolation.

Step-c) involves the reaction of compound of Formula III with methanesulfonyl chloride to provide the compound of Formula IV.

In embodiments of step c), the reaction may be carried out in a suitable inert solvent. Examples of such solvents include ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, chlorobenzene or dichlorobenzene or their mixture thereof.

In embodiments of step c), the reaction can be carried out in the presence of a base. Any of the bases listed in step b) can be used in this step.

In embodiments of step c), the reaction can be carried out at a temperature ranging from about -10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 0°C to 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.

In embodiments of step c), the compound of Formula IV can be prepared by dissolving the compound of Formula III in tetrahydrofuran followed by the addition of triethylamine and 4-dimethylaminopyridine. The solution of methanesulfonyl chloride in tetrahydrofuran is added to the reaction mixture at 0°C.

In embodiments of step c), the compound of Formula IV may be isolated directly from the reaction mixture itself after the reaction is complete or may be used in the next step without isolation.

Step-d) involves the preparation of dapoxetine by reacting the compound of Formula IV with dimethylamine.

In embodiments of step d), dapoxetine can be prepared by adding dimethylamine to the solution containing compound of Formula IV. The dimethylamine may be used in the form of dimethylamine gas, dimethylamine hydrochloride, or aqueous solution of dimethylamine.

In embodiments of step d), the reaction may be carried out in the presence of an inert solvent. The solvents which are described in step-c may be used for this step.

In embodiments of step d), the reaction can be carried out at a temperature ranging from about -10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 0°C to 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.

In embodiments of step d), dapoxetine may be isolated directly from the reaction mixture itself after the reaction is complete in step (d), or after conventional work up with known techniques.

In embodiments of step d), dapoxetine is optionally isolated by extracting in a solvent followed evaporation of the solvent.

In embodiments of step d), dapoxetine can be optionally purified by any method known in the art such as recrystallization involving single solvent, mixture of solvents, or solvent-anti solvent technique; slurring in a solvent; or chromatography to improve its chemical purity. The methods known in the art can be used for the isolation and drying of dapoxetine after purification.

In embodiments of step d), dapoxetine may be converted to dapoxetine hydrochloride without isolation i.e., in situ.

In embodiments of step e), dapoxetine is converted into dapoxetine hydrochloride in the presence of a source of hydrogen chloride.

In embodiments of step e), dapoxetine can be dissolved in any suitable inert solvent. Examples of such solvents include but are not limited to ethers, such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, dioxane or dimethoxyethane; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone; ester solvents such as ethyl acetate, propyl acetate or butyl acetate; alcohol solvents such as methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, or Ci-C6 alcohols; carboxylic acid solvents such as acetic acid or propionic acid; or nitrile solvents such as acetonitrile or propionitrile; or mixture of the said solvents.

In embodiments of step e), solution of dapoxetine can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent, or about 0°C to about 80°C. Dapoxetine solution can also be obtained from the reaction mass of the previous stage during its synthesis.

In embodiments of step e), dapoxetine solution obtained above can be added dropwise or lot wise in a single lot or in parts to a source of hydrogen chloride or vice versa. In embodiments of step e), a source of hydrogen chloride can be hydrochloric acid such as concentrated hydrochloric acid or aqueous diluted hydrochloric acid, hydrogen chloride gas, an organic solvent hydrochloride such as methanol hydrochloride, ethanol hydrochloride, isopropyl alcohol hydrochloride, ethyl acetate hydrochloride, methyl tertiarybutylether hydrochloride an acid chloride such as acetyl chloride.

In embodiments of step e), the addition of dapoxetine solution or a source of hydrogen chloride to the other can be done at any suitable temperatures, such as from about -10°C to about 80°C or from about 0°C to about 60°C.

In embodiments of step e), the reaction mass obtained can be maintained for a time from about 1 hour to about 20 hours, or longer.

In embodiments of step e), dapoxetine hydrochloride produced in the reaction can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or evaporation of solvent or the like, and optionally washing the resulting solid with a solvent. In one embodiment, the washing is with the solvent used in the above reaction.

In embodiments of step e) dapoxetine hydrochloride that is isolated can be dried at suitable temperatures, such as from about 40°C to about 100°C and suitable pressures from about 1 hour to about 15 hours or longer, using drying equipment known in the art, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. Drying temperatures and times will be sufficient to achieve desired product purity.

Another aspect of the application provides a process for the preparation of dapoxetine hydrochloride compound of Formula I, which comprises:

a) reacting methyl cinnamate with R-(+)-N-Benzyl-a-methylbenzylamine of Formula VI:

Formula VI to provide a compound of Formula VII;

Formula VII

b) debenzylating the compound of Formula VII obtained in step a) to provide a compound of Formula VIII;

Formula VIII

c) reducing the compound of Formula VIII obtained in step b) to provide a compound of Formula IX;

Formula IX

d) N-methylating the compound of Formula IX obtained in step c) to provide a compound of formula X;

Formula X
e) reacting the compound of Formula X obtained in step d) with 1-fluoronaphthalene to provide dapoxetine; and

f) converting dapoxetine obtained in step e) to dapoxetine hydrochloride in presence of a source of hydrogen chloride.

According to the aspect of the application, the preparation of dapoxetine hydrochloride as described above as shown in the scheme-2.

Scheme-2
Step-a) involves the reaction of methyl cinnamate with R-(+)-N-Benzyl-a-methylbenzylamine to provide a compound of Formula VII.

In an embodiment step-a) the reaction of methyl cinnamate with R-(+)-N-Benzyl-a-methylbenzylamine may be carried out in the presence of a base and a solvent to provide a compound of Formula VII.

In an embodiment step-a), the reaction may be carried out in a suitable inert solvent. Examples of such solvents include but are not limited to ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, chlorobenzene or dichlorobenzene or their mixture thereof.

In embodiments of step a), the reaction can be carried out in the presence of a base. Bases that are useful in the reaction include, but are not limited to: lithium hydride, sodium hydride, potassium hydride, or the like; n-butyl lithium etc.

In embodiments of step a), the reaction can be carried out at a temperature ranging from about -90°C to 0°C of the solvent. In one embodiment, the reaction can be carried out from about -80°C to -10°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of for about 1 to about 24 hours or longer.

In embodiments of step a), the product may be isolated directly from the reaction mixture itself after the reaction is complete, or after conventional work up with techniques such as quenching with a suitable reagent, extraction, or the like.

In embodiments of step a) the product of step-a), i.e., compound of Formula VII is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation.

In embodiments of step a) the product of step-a), i.e., compound of Formula VII may be used in the next step without isolation.

Step b) involves the debenzylation of compound of Formula VII to provide a compound of Formula VIII.

In an embodiment of step b), the debenzylation of compound of Formula VII may be carried out in the presence of a solvent and a debenzylating agent.

In an embodiment of step b), the debenzylation may be carried out in the presence of a noble metal catalyst and hydrogen gas, a phase transfer hydrogenation, or other deprotecting reagents. Other deprotecting agents include mineral acids, strong acids, Lewis acids, aqueous mineral bases. The deprotecting agents may be present in a suitable solvent. The debenzylation can be carried out in the presence of a noble metal catalyst and hydrogen gas. The catalyst may be selected from the group consisting of palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, platinum, platinum on activated carbon and Raney™ nickel in solvents such as methanol, ethanol, water, dioxane, tetrahydrofuran, acetic acid, ethyl acetate, dichloromethane, chloroform, dimethyl formamide, or mixtures thereof.

In an embodiment of the step b), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 10°C to 40°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of for about 1 to about 24 hours or longer.

In embodiments of step b), the product may be isolated directly from the reaction mixture itself after the reaction is complete, or after conventional work up with techniques such as quenching with a suitable reagent, extraction, or the like.

In embodiments of step b), the product of step-b), i.e., compound of Formula VIM is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation.

In embodiments of step b) the product of step-b) i.e., compound of Formula VIII may be used in the next step without isolation.

Step c) involves the reduction of compound of Formula VIM to provide a compound of Formula IX. In embodiments of step-c) the reduction of compound of Formula VIM may be carries out in the presence of a solvent and a reducing agent to provide a compound of Formula IX.

In embodiments of step c), the reduction may be carried out by using a suitable reducing agent. The reducing agents which may be used but are not limited to Sodium borohydride, Potassium borohydride, Lithium aluminium hydride, Vitride® or Red-AI®, borohydrides in the presence of iodine or lewis acids etc.

In embodiments of step c), the reaction may be carried out in a suitable inert solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of such solvents include tetrahydrofuran, methanol or water or their mixture thereof.

In embodiments of step c), the reaction can be carried out at a temperature ranging from about -10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 0°C to room temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of about 1 to about 24 hours or longer.

In embodiments of step c), the product may be isolated directly from the reaction mixture itself after the reaction is complete, or after conventional work up with techniques such as quenching with a suitable reagent, extraction, or the like.

In embodiments of step c), the product of step-c), i.e., compound of Formula IX is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. In embodiments of step c) the product of step-c) i.e., compound of Formula IX may be used in the next step without isolation.

Step d) involves the N-methylation of compound of Formula IX to provide a compound of Formula X. In an embodiment of step d) the N-methylation of compound of Formula IX can be carried out by using any suitable methylating agent. In an embodiment of step d) the N-methylation is carried out by using formalin and formic acid.

In an embodiment of step d) the reaction may be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 50°C to 100°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of about 1 to about 24 hours or longer.

In embodiments of step d), the product may be isolated directly from the reaction mixture itself after the reaction is complete, or after conventional work up with techniques such as quenching with a suitable reagent, extraction or the like.

In embodiments of step d), the product of step-d i.e., compound of Formula X is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. In embodiments of step d), the product of step-d), i.e., compound of Formula X may be used in the next step without isolation.

Step-e) involves the preparation of dapoxetine by reacting the compound of Formula X with 1-fluoronaphthalene.

In embodiments of step e), the reaction can be carried out in the presence of a base. Bases that are useful in the reaction include, but are not limited to: inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, or alkoxides, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, barium hydroxide, calcium oxide, or alkali metal hydrides e.g. sodium hydride, potassium hydride, or the like; or organic bases such as, for example, tertiary amines, e.g., triethylamine, N,N-dimethylethanolamine, N,N-diethylethanolamine, 4-ethylmorpholine, 1,4-diazabicyclo[2.2.2]-octane, N-methyl morpholine, dimethylaminopyridine, diisopropylamine, diisopropylethylamine, pyridine, or the like.

In embodiments of step e), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 5°C to 90°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.

In embodiments of step e), the product may be isolated directly from the reaction mixture itself after the reaction is complete in step (d), or after conventional work up with techniques such as quenching with a suitable reagent, extraction, or the like.

In embodiments of step e), the product of step-e), i.e., dapoxetine is optionally isolated by extracting in a suitable solvent followed by removal of the solvent by evaporation.

In embodiments of step e), dapoxetine can be optionally purified by any method known in the art such as recrystallization involving single solvent, mixture of solvents, or solvent-anti solvent technique; slurring in a solvent; or chromatography to improve its chemical purity. The methods known in the art can be used for the isolation and drying of dapoxetine after purification.

In embodiments of step e), dapoxetine may be converted to dapoxetine hydrochloride without isolation i.e., in situ.

The dapoxetine obtained from step-e) may be converted to dapoxetine hydrochloride by following the procedures described herein the application.

Another aspect of the application provides a process for the preparation of dapoxetine hydrochloride of Formula I, which comprises:

a) reducing D-phenylglycine followed by N-Boc protection or reducing N-Boc-D-
phenylglycine to provide a compound of Formula XI;

Formula XI

b) reacting the compound of Formula XI obtained in step a) with methanesulfonyl chloride to provide a compound of Formula XII;

Formula XII
c) treating the compound of Formula XII obtained in step b) with sodium cyanide to provide a compound of Formula XIII;

Formula XIII

d) hydrolyzing the compound of Formula XIII obtained in step c) in presence of a base to provide a compound of Formula XIV;

Formula XIV

e) reducing the compound of Formula XIV obtained in step d) to provide a compound of Formula XV;

Formula XV

f) deprotecting the compound of Formula XV obtained in step e) using acid to produce a compound of Formula IX;

Formula IX

g) N-methylating the compound of Formula IX obtained in step f) to produce a compound of Formula X; h) reacting the compound of Formula X obtained in step g) with 1- fluoronaphthalene to provide dapoxetine; and i) converting dapoxetine obtained in step h) to dapoxetine hydrochloride in presence of a source of hydrogen chloride.

In another aspect of the application, the compound of Formula IX can be prepared by the process comprises,

a) hydrolyzing the compound of Formula XIII in presence of acid to produce the compound of Formula XVI,

Formula XVI

b) reducing the compound of Formula XVI obtained in step a) to provide the compound of Formula IX.

According to the aspect of the application, the preparation of dapoxetine hydrochloride is as described in the scheme-3.

Scheme-3

Step a) involves the preparation of compound of Formula XI by the reduction of D-phenylglycine followed by the protection of amine group.

In embodiment of step a), the reduction of D-phenylglycine may be carried out by using a suitable reducing agent. The reducing agents which may be used but are not limited to Sodium borohydride, Potassium borohydride, Lithium aluminium hydride, Vitride® or Red-AI®, borohydrides in the presence of iodine or lewis acids etc.

In embodiment of step a), the product which is obtained by the reduction can be protected with Boc-anhydride in situ.

In embodiment of step a), the reaction may be carried out in a suitable inert solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of such solvents include ethers, such as tetrahydrofuran, alcohols such as methanol, water, or their mixture thereof.

In embodiments of step a), the compound of Formula XI may be prepared by reducing D-phenylglycine with sodium borohydride and iodine in tetrahydrofuran followed by the protecting amine group with Boc-anhydride.

In embodiments of step a), the reaction can be carried out at a temperature ranging from about -10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 0°C to 60°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of about 1 to about 24 hours or longer.

In embodiments of step a), the product may be isolated directly from the reaction mixture itself after the reaction is complete, or after conventional work up with techniques such as quenching with a suitable reagent, extraction, or the like.

In embodiments of step a), the product of step a) i.e., the compound of formula XI is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation.

In embodiments of step a), the product of step-a) i.e., compound of Formula XI may be used in the next step without isolation.

In another embodiment of step a), the compound of Formula XI can also be prepared by reducing the Boc-protected D-phenylglycine in tetrahydrofuran with the procedure described above.

Step b) involves the reaction of compound of Formula XI with methanesulfonyl chloride to provide the compound of Formula XII.

In embodiments of step b), the process that is described in the present application for the similar reaction i.e., mesylation step can be used for this step also.

In embodiments of step b), the product of step b) can be isolated or can be used for the next step without isolation i.e., in situ.

Step c) involved the cyanation of compound of Formula XII to provide a compound of Formula XIII.

In embodiment of step-c), cyanation may be carried out by using a suitable cyanating agent such as sodium cyanide or potassium cyanide. In embodiment of step c), cyanation can be carried out by using sodium cyanide.

In embodiment of step-c), cyanation may be carried in a suitable inert solvent. The reaction can be carried out in an aprotic polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or dimethylsulfoxide, nitriles such as aectonitrile or propionitrile, aromatic hydrocarbons such as toluene, or chlorobenzene or the like.

In embodiments of step c), the reaction can be carried out at a temperature ranging from about -10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 0°C to 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.

In embodiments of step c), the product obtained from the step-c) can be isolated by the techniques known in the art or the techniques described in the present application.

In embodiments of step c), the product of step-c), i.e., compound of Formula XIII may be used in the next step without isolation.

Step d) involves the hydrolysis of compound of Formula XIII with a base to provide a compound of Formula XIV.

In embodiment of step d), the hydrolysis may be carried in presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate in a suitable solvent. The solvents that can be used but not limited to; alcohols such as methanol, ethanol, 1-propanol, isopropanol or water or their mixtures.

In embodiments of step d), the reaction can be carried out at a temperature ranging from about 40°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 40°C to 100°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of for about 1 to about 24 hours or longer.

In embodiments of step d), the product obtained from the step-d), can be isolated by the techniques known in the art or by the techniques described in the present application.
In embodiments of step d), the product of step-d), i.e., compound of Formula XIV may be used in the next step without isolation.

Step e) involves the reduction of compound of Formula XIV to provide a compound of Formula XV.

In embodiment of step e) the reaction is carried out by using reducing agents such as lithium aluminium hydride, sodium borohydride, or Vitride® in presence of a solvent such as tetrahydrofuran, methanol, water, or their mixtures. The compound of Formula XV may be isolated by the techniques known in the art or the techniques described in the present application. The procedures described above for the similar reduction can also be employed for this reduction step.

In embodiments of step e), the product of step-e), i.e., compound of Formula XV may be used in the next step without isolation.

Step f) involves the deprotection of compound of Formula XV to provide a compound of Formula IX.

In embodiment of step f), the deprotection is carried out by using mineral acids such as hydrochloric acid, hydrobromic acid in the presence of a solvent such as water, methanol, ethanol, or their mixtures with water. The compound of Formula IX may be isolated by the techniques known in the art or the techniques described in the present application.

In embodiments of step f). the product of step-f), i.e., compound of Formula IX may be used in the next step without isolation.

In another aspect of the application, the compound of Formula IX can also prepared by the process which comprises:

a) hydrolyzing the compound of Formula XIII in presence of acid to produce the compound of Formula XVI; and

Formula XVI
b) reducing the compound of Formula XVI obtained in step a) to provide the compound of Formula IX.

Step a) involves the hydrolysis of compound of Formula XIII with acid to provide the compound of Formula XVI.

In embodiments of step a), the hydrolysis of compound of Formula XIII may be carried out using mineral acids such as hydrochloric acid, hydrobromic acid.

In embodiments of step a), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 60°C to 100°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.

In embodiments of step a) the product may be isolated directly from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as quenching with a suitable reagent, extraction or the like.

In embodiments of step a), the product of step-a) i.e., compound of Formula XVI is optionally isolated by extracting in a suitable solvent followed by neutralization and removal of the solvent by filtration.

Step b) involves the preparation of compound of Formula IX by the reduction of compound of Formula XVI,

In embodiment of step b), the reaction is carried out by the procedures described herein for a similar reduction step.

The conversion of compound of formula IX to dapoxetine or dapoxetine hydrochloride can be carried out using the procedures described in the present application.

Another aspect of the application provides a process for the preparation of highly pure (+) dapoxetine or an acid addition salt thereof, which comprises:

a) resolving racemic dapoxetine with a chiral acid so as to obtain a chiral acid salt of (+)-dapoxetine;

b) converting the chiral acid salt of (+)-dapoxetine prepared in step (a) to (+)-dapoxetine; and

c) optionally converting the (+)-dapoxetine obtained in step b) into an acid addition salt.

In embodiments, highly pure Dapoxetine or its acid addition salt means having purity more than 99.5% or more than 99.8% or more than 99.9% measured by HPLC. In embodiments, highly pure Dapoxetine or its acid addition salt means having chiral purity more than 99.5% or more than 99.8% or more than 99.9% measured by HPLC.

Step a) involves the resolution of racemic dapoxetine with a chiral acid to obtain a chiral acid salt of (+)-dapoxetine. The resolution may be carried out with a suitable chiral acid in a suitable solvent.

In embodiment of step a), the chiral acid may be selected from the group comprising of mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid, or the like. Other suitable chiral acids may be determined by testing and use thereof in a process as described above falls within the scope of the present application.

In an embodiment of step a), the resolution is carried out in a suitable solvent. The solvent that may be used but not limited to aliphatic halogenated lower alkanes, cyclic or acyclic alkenes, lower alcohols, ketones etc, although again the other suitable solvents can be determined by testing and the use thereof in a process as described above falls within the scope of the present application.

In an embodiment of step a), the chiral acid salts of (+)-dapoxetine obtained according to the process of the present application are substantially free of (-) dapoxetine. In an embodiment of step a), the chiral acid salts of (+)-dapoxetine obtained according to the process of the present application is having chiral purity greater than 90% ee and chemical purity greater than 98%.

In an embodiment of step a), the chiral acid salts of (+)-dapoxetine obtained according to the process of the present application can be further purified to enhance the chemical purity and chiral purity by the methods known in the art such as crystallization, recrystallization, column chromatography, slurry wash etc.

In an embodiment of step b), intermediate chiral salts prepared according to the present application as described above can be converted to the free base or another acid addition salt. An intermediate salt of the chiral acid and (+)-dapoxetine can be treated with a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate etc. to obtain the free base. The free base itself can, if desired, be converted into an acid addition salt thereof.

In an embodiment of step c), suitable acid addition salts which may be formed include those formed with pharmaceutical^ acceptable organic or inorganic acids and are well known to those of skill in the art. Acids commonly used to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric or phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, methanesulfonic, oxalic, para-bromophenyl sulfonic, carbonic, succinic, citric, benzoic or acetic acid, or related inorganic or organic acids. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid or hydrobromic acid, or those formed with organic acids such as oxalic acid or maleic acid. A pharmaceutical^ preferred acid addition salt is the hydrochloride.

The conversion of dapoxetine to dapoxetine hydrochloride can be carried out using the procedures described above.

In an aspect of the application, dapoxetine hydrochloride obtained by the methods of the present application can be further purified by using techniques known in the art to enhance its chemical purity and chiral purity.

Potential impurities possible in Dapoxetine hydrochloride are the unreacted starting materials and intermediates, described in the present application. Possible impurities in Dapoxetine hydrochloride, in addition to unreacted starting materials or intermediates described in the present application can have structural formula as illustrated below.

In embodiments, dapoxetine hydrochloride obtained according to the processes described in the present application may be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills.

In an aspect the application provides a pharmaceutical composition comprising dapoxetine hydrochloride obtained according to the processes described in the present application along with one or more pharmaceutically acceptable carriers, excipients, or diluents.

In embodiments, racemic dapoxetine used in the present application may be obtained from any process known in the art.

The scope of present application is not limited by the description, examples and suggested uses described herein and modifications can be made without departing from the spirit of application.

DEFINITIONS

The following definitions are used in connection with the disclosure of the present application, unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated "Cx-Cy", where x and y are the lower and upper limits, respectively. For example, a group designated as "C1-C6" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions or the like.

The term "reacting" is intended to represent bringing the chemical reactants together under conditions that cause the chemical reaction indicated to take place.

The following abbreviations and acronyms are used herein and have the indicated definitions: "Boc anhydride" is intended to represent di-tert-butyl dicarbonate in the present application and Boc is the t-butoxycarbonyl radical.

"Vitride®" used in the present application is intended to represent Sodium Dihydrobis(2-methoxyethoxy) aluminate.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the application described and claimed herein.

While particular embodiments of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the application. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this application.

EXAMPLES
Example 1:
Preparation of (R)-3-chloro-1-phenylpropan-1-ol (Compound of Formula II): (+) Diisopinocampheylchloroborane (18.0 g) and dichloromethane (100 ml_) are charged in to round bottom flask at 26°C and stirred to get a clear solution. The reaction is cooled to 0°C. A solution of 3-chloro-1-phenylpropan-1-one (6.0 g) in dichloromethane (80 mL) is added to the reaction mass dropwise at 0°C in 25 minutes. The temperature of the reaction mass is allowed to rise at 26°C and stirred at the same temperature for 14 hours. Progress of the reaction is monitored by TLC. After completion, the reaction is quenched with aqueous solution of acetic acid at 0°C. Water (150 mL) is added to the reaction mass and stirred for 15 minutes at 26°C. The organic and aqueous layers are separated. The organic layer is washed with water (150 mL X2) and brine solution (150 mL). The organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure to produce the title compound. Chiral HPLC: 97.43%

Example 2:
Preparation of (R)-3-(naphthalen-1-yloxy)-1 -phenylpropan-1-ol (compound of Formula III): N, N-Dimethylformamide (30 mL) and (R)-3-chloro-1-phenylpropan-1-ol (from example-1) are charged into a round bottom flask at 26°C and stirred to get a clear solution. Potassium carbonate (5.33 g) and 1-naphthol (4.05 g) are added to the reaction mass at 26°C. The reaction mass is heated to 80°C and stirred for 8 hours. Progress of the reaction is monitored by TLC. The reaction mass is cooled to 10°C and ice cold water (100 mL) is added. The reaction mass is extracted with ethyl acetate (80 mL X2). The organic and aqueous layers are separated. The organic layer is washed with water (150 mL), 2M NaOH aqueous solution (100 mL), and brine solution (120 mL). The organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure to produce the title compound. Yield: 6.0 g, Chiral HPLC: 96.67%

Example 3:
Preparation of dapoxetine hydrochloride (compound of Formula I): Tetrahydrofuran (175 mL) and (R)-3-(naphthalen-1-yloxy)-1-phenyl propan-1-ol (25 g) are charged into a round bottom flask at 25°C and stirred to get a clear solution under nitrogen. Triethylamine (18.19 g) and 4-dimethylaminopyridine (1.09 g) are added to the reaction mass at 25 °C. The reaction mass is cooled to 0°C. The solution of methanesulfonyl chloride (15.45 g) in Tetrahydrofuran (75 mL) is added dropwise to the reaction mass in 25 minutes at 0°C and stirred for 3 hours at the same temperature under nitrogen. Progress of the reaction is monitored by TLC. After completion of the reaction, dimethylamine gas is purged to the reaction mass at for 1 hour 30 minutes at -5°C and the reaction vessel is sealed and stirred for 16 hours at room temperature. After completion of the reaction, water (750 mL) is added to the reaction mass, the pH adjusted to 11-12 with 5N sodium hydroxide and extracted with ethyl acetate (400 mL). The organic and aqueous layers are separated. The organic layer is washed with water (400 mL X2). The organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure to produce crude dapoxetine.

The crude dapoxetine is dissolved in ethyl acetate (125 mL) and solution is cooled to 10°C. The solution of hydrogen chloride in ethyl acetate is added till the pH 2 is obtained. The reaction mass is stirred at 20-25°C for 30 minutes. The precipitated product is filtered and washed with mixture of ethyl acetate and hexane (50 mL+50 mL). The obtained solid material is dried under vacuum. Yield: 27.0 g, HPLC purity: 99.25% and Chiral purity: 99.22%.

Example 4:
Preparation of compound of Formula VII: R-(+)-N-Benzyl-a-methylbenzylamine (72.97 g) and THF (875 mL) are charged into a round bottom flask at 25° under nitrogen. The reaction mass is cooled to -78°C by using dry ice and acetone bath. N-Butyl lithium (216 mL) is added dropwise to the reaction mass at -78 °C in 50 minutes and maintained at the same temperature for 45 minutes. The solution of methyl cinnamate (35 g) in THF (175 mL) is added dropwise to the reaction mass at -78 °C in 25 minutes and maintained at the same temperature for 2 hours. Progress of the reaction is monitored by TLC. After completion, the reaction mass is quenched with saturated solution of ammonium chloride at -78°C and allowed the reaction mass to room temperature in 30-40 minutes. The organic and aqueous layers are separated. The aqueous layer is extracted with ethyl acetate (200 mL). The organic layer is washed with brine (700 mL). The organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure to obtain the title compound as crude yellow syrup. The crude product is purified by column chromatography using ethyl acetate and hexane as elute. Yield: 58.0 g. Chiral purity: 99.72 %.

Example 5:
Preparation of (S)-methyl 3-amino-3-phenylpropanoate (compound of formula VIII): Acetic acid (470 mL) and compound of formula VII (57.0 g) from the previous example are added into hydrogenation flask at 26°C. A suspension of 10% palladium on carbon in acetic acid (100 mL) is added to the flask at 26°C. The hydrogenation flask containing the reaction mass is fitted to a Parr shaker apparatus. The reaction mass is shaken under hydrogen pressure (60 psi) for 14 hours at 26°C. After completion, the reaction mass is filtered on Celite. The filtrate is concentrated under reduced pressure at 60°C to get a residue. Water (400 mL) is added to the residue and neutralized with saturated solution of sodium bicarbonate and extracted with ethyl acetate (250 mL X2). The organic layer is washed with brine (350 mL). The organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure to obtain the title compound as brown syrup. Yield: 15.5 g.

Example 6:
Preparation of (S)-3-amino-3-phenylpropan-1-ol (compound of formula IX): Tetrahydrofuran (225 mL) and lithium aluminium hydride (4.77 g) are charged into a round bottom flask under nitrogen and cooled to 0°C. (S)-Methyl 3-amino-3-phenylpropanoate (15 g) dissolved in THF (150 mL) is added to the reaction mass at 0°C in 30 minutes. The temperature of the reaction mass is raised to 20°C and stirred at the same temperature for 2 hours. The reaction mass is quenched with saturated solution of sodium sulfate and filtered through Celite®. The filtrate is extracted with ethyl acetate (50 mL X2). The organic layer is washed with brine (300 mL) and dried over sodium sulfate. The solvent is evaporated under reduced pressure to obtain the title compound as brown syrup. Yield: 12 g.

Example 7:
Preparation of (S)-3-(dimethylamino)-3-phenylpropan-1-ol (compound of formula X): (S)-3-Amino-3-phenylpropan-1-ol (11.6 g) is charged into a round bottom flask at 26°C. Formalin (37%, 20.3 mL) is added to the reaction mass at 26°C and stirred for 10 minutes. Formic acid (85%, 13.2 mL) is added to the reaction mass and heated to 90°C and stirred for 10 hours at same temperature. Progress of the reaction is monitored by TLC. After completion, water (40 mL) is added to the reaction mass and pH adjusted to 2 with 6N HCI. The reaction mass is washed with dichloromethane (100 mL X2). The layers are separated and the aqueous layer is neutralized with sodium bicarbonate solution. The aqueous layer is extracted with ethyl acetate (90 mL X2) and with dichloromethane (100 mL). The organic layer is washed with brine (150 mL) and dried over sodium sulfate. The solvent is evaporated under reduced pressure to obtain the title compound as yellow syrup. Yield: 9.6 g.

Example 8:
Preparation of (S)-N, N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine (compound of formula V): Dimethyl acetamide (90 mL) and sodium hydride (7.83 g) are charged into a round bottom flask at 26°C under nitrogen. The solution of (S)-3-(dimethylamino)-3-phenylpropan-1-ol (9.0 g) in dimethyl acetamide (90 mL) is added to the reaction mass at 26°C. The reaction mass is heated to 60°C and stirred for 30 minutes at the same temperature. 1-Fluoronaphthalene (8.8 g) is added to the reaction mass at 60°C and raised the temperature to 90°C. The reaction mass is stirred at 90°C for 3 hours. Progress of the reaction is monitored by TLC. After completion of the reaction, reaction mass is cooled to 10°C and cold water (300 mL) is added. The pH of the reaction mass is adjusted to 2 with 6N HCI. The reaction mass is washed with ethyl acetate. The aqueous layer is cooled to 0°C and adjusts pH-7 to 8 with saturated solution of sodium bicarbonate and extracted with ethyl acetate (140 mL X3). The organic layer is washed with cold water (240 mL X3) and dried over sodium sulfate. The solvent is evaporated under reduced pressure to obtain the title compound as brownish yellow syrup. Yield: 8.0 g.

Example 9:
Preparation of dapoxetine hydrochloride: Dapoxetine (7.8 g) and methyl tertiary butyl ether (78 mL) are charged into a round bottom flask at 26°C under nitrogen. The solution is cooled to 10°C and the solution of hydrogen chloride in methyl tertiary butyl ether (16 mL) is added by drops at 10°C in 25 minutes. The reaction mass is stirred for 20 minutes at the same temperature. The solid compound is isolated by filtration and washed with methyl tertiary butyl ether (20 mL X2).The solid material and isopropyl alcohol are added to round bottom flask. The suspension was heated to dissolve and reflux for 15 minutes. The reaction mass is cooled to room temperature within 1 hour and further cooled to 10°C and stirred for 15 minutes. The solid compound is isolated by filtration and washed with isopropyl alcohol. The material is dried under vacuum. Yield: 4.7 g, chiral purity: 99.88%, HPLC purity: 98.60%

Example 10:
Preparation of (R)-tert-butyl (2-hydroxy-1-phenylethyl)carbamate (compound of Formula XI): Sodium borohydride (30 g) and THF (500 mL) are charged into round bottom flask at 27°C. The reaction mass is cooled to 0°C. The solution of iodine (100.9 g) in THF (150 mL) is added dropwise to the reaction mass at 0°C for 1 hour 30 minutes and stirred for same temperature for 15 minutes. D-phenyl glycine (50 g) is added to the reaction mass at 0°C. The temperature of the reaction mass is raised to 65°C and stirred for 18 hours at reflux. Progress of the reaction is monitored by TLC. After completion, the reaction mass is cooled to 0°C. Then methanol (80 mL) is added dropwise at 0°C and diluted with THF. Triethylamine (40.3 g) is added to the reaction mass at 0°C. Boc-anhydride (79.5) is added dropwise to reaction mass at 0°C. The temperature of the reaction mass is allowed to rise to 25°C and stirred for 30 minutes. After completion of the reaction, water (1000 mL) is added and extracted with ethyl acetate (500 mL X2). The layers are separated and organic layer washed with sodium bicarbonate solution (500 mL X2) and brine solution (500 mL). The organic layer is dried over sodium sulfate. The solvent is evaporated completely under reduced pressure to obtain the residue. The residue is dissolved in dichloromethane (800 mL) and heated to reflux. Hexane (500 mL) is added to the solution and cooled to 10°C. The solid compound is isolated by filtration and washed with chilled hexane (50 mL). Yield: 35 g.

Example 11:
Preparation of (R)-tert-butyl(2-hydroxy-1-phenylethyl) carbamate (compound of Formula XI): Tetrahydrofuran (500 mL) and N-Boc-D-phenyl glycine (50 g) are charged into round bottom flask at 25°C under nitrogen. The reaction mass is stirred to get clear solution at 25°C. The reaction mass is cooled to 0°C. Vitride® (70% in toluene) (172.4 mL) is added slowly to the reaction in 45 minutes mass at 0°C. The reaction mass is stirred for 1 hour at 0°C. After completion, the reaction is slowly quenched with 10% sodium potassium tartrate solution (500 mL) and extracted with ethyl acetate (2 X 300 mL). The layers are separated and organic layer washed with brine solution (2 X 500 mL) and dried over sodium sulfate. The solvent is evaporated completely under reduced pressure to obtain the titled compound as off white color solid. Yield: 38.2 g; HPLC purity: 99.79%; and chiral HPLC purity: 98.79%.

Example 12:
Preparation of (R)-2-((tert-butoxycarbonyl)amino)-2-phenylethyl methanesulfonate (compound of Formula XII): Dichloromethane (350 mL) and (R)-tert-butyl (2-hydroxy-1-phenylethyl)carbamate (35 g) are charged into round bottom flask at 25 °C under nitrogen. Triethylamine (29.8 g) is added to the reaction mass and cooled to 0°C. Methanesulfonyl chloride (25.4 g) is added dropwise to the reaction mass at 0°C in 30 minutes. The reaction mass is stirred at the same temperature for 1 hour. After completion, the reaction mass is quenched with sodium bicarbonate solution (250 mL). The layers are separated and the aqueous layer is extracted with dichloromethane (100 mL X2). The organic layer washed with brine (300 mL X2) and dried over sodium sulfate. The solvent is distilled out completely to get the crude. The crude material is slurried in hexane and filtered to get the title compound as an off white solid. Yield: 46 g

Example 13:
Preparation of (S)-tert-butyl (2-cyano-1-phenylethyl) carbamate (compound of Formula XIII): Dimethylsulfoxide (460 mL) and (R)-2-((tert-butoxycarbonyl)amino)-2-phenylethyl methanesulfonate (46 g) are charged into round bottom flask at 27°C and stirred to get a clear solution. Sodium cyanide (21.46 g) is added to the reaction mass at 27°C. The reaction mass is heated to 45°C and stirred at the same temperature for 18 hours. Progress of the reaction is monitored by TLC. The reaction mass is cooled to 27 °C and water (1.5 L) added. The solid compound is obtained by the filtration and washed with chilled water. The material is dried under vacuum oven at 50°C. Yield: 29 g.

Example 14:
Preparation of (S)-3-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (compound of Formula XIV): Ethanol (350 mL) and (S)-tert-butyl (2-cyano-1-phenylethyl)carbamate (35 g) are charged into round bottom flask at 27°C and stirred to get a clear solution. The solution of sodium hydroxide (17 g) in water (100 mL) is added to the reaction mass at 27°C.The reaction mass is heated to 90°C and stirred at the same temperature for 4 hours. Progress of the reaction is monitored by TLC. The solvent form the reaction mass is distilled completely to obtain residue. Water is added to the residue and saturated citric acid solution is added to adjust pH 6.0 to 6.5 and stirred for 20 minutes. The solid compound is obtained by filtration and washed with chilled water. The material is dried under vacuum oven at 50°C. Yield: 24.2 g.

Example 15:
Preparation of (S)-tert-butyl (3-hydroxy-1-phenylpropyl) carbamate (compound of Formula XV): Tetrahydrofuran (480 mL) and (S)-3-((tert-butoxycarbonyl) amino)-3-phenylpropanoic acid (48 g) are charged into round bottom flask at 27°C. The reaction mass is cooled to 0°C. Vitride® (70% solution in toluene) 156.8 mL is added to the reaction mass at 0°C in 45 minutes and stirred for 1 hour at the same temperature. Progress of the reaction is monitored by TLC. After completion, the reaction mass is quenched with 10 % solution of potassium tartarate and sodium tartrate. The reaction mass is stirred with ethyl acetate (500 mL X2). The organic layer washed with brine (500 mL X2) and dried over sodium sulfate. The solvent is distilled out completely to get the product as a pale yellow liquid. Yield: 409-

Example 16:
Preparation of (S)-3-amino-3-phenylpropan-1-ol (compound of formula IX): (S)-tert-Butyl (3-hydroxy-1-phenylpropyl)carbamate and 6N HCI (280 mL) are charged into round bottom flask at 27°C. The reaction mass is heated to 70°C and stirred at the same temperature for 3 hours. Progress of the reaction is monitored by TLC. The reaction mass is cooled to 20°C and reaction mass is extracted with dichloromethane (100 mL X2).The aqueous layer is cooled to 15°C and neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate (150 mL X2). The organic layer washed with brine (300 mL) and dried over sodium sulfate. The solvent is distilled out completely to get the product as a pale yellow thick liquid. Yield: 15.3 g.

Example 17:
Preparation of (S)-3-amino-3-phenylpropanoic acid (compound of formula XVI): (S)-tert-Butyl (2-cyano-1-phenylethyl)carbamate (53 g) and 6N hydrochloric acid (1060 mL) are charged into round bottom flask at 26°C. The reaction mass is slowly heated to 110°C and stirred for 16 hours at the same temperature. After completion, the reaction mass is cooled to 20°C and washed with dichloromethane (450 mL). The layers are separated. The aqueous layer is concentrated on rotavapour to obtain crude. Acetone (225 mL) is charged in crude material and cooled to 10°C. Aqueous sodium hydroxide solution (50 % w/v) is added till pH 5.5 to 6. The solid material is collected by filtration and washed with acetone. The material is dried under vacuum. Yield: 46.0 g.

Example 18:
Preparation of (S)-3-amino-3-phenylpropan-1-ol (compound of formula IX): (S)-3-Amino-3-phenylpropanoic acid (45 g) and dry tetrahydrofuran (450 mL) are charged into round bottom flask under nitrogen at 26°C. The reaction mass is stirred at the same temperature for 10 minutes. The reaction mass is cooled to 0°C. Vitride® solution [198 mL (70% in toluene)] is added to the reaction mass in 45 minutes at 0°C. The reaction mass is stirred for 1 hour at 3°C. After completion, the reaction mass is quenched with 10 % potassium sodium tartarate solution (500 ml). The reaction mass is extracted with ethyl acetate (2 X 300 mL) and separated the layers. The organic layer is washed with brine (2 X 400 mL) and dried over sodium sulfate. The solvent is distilled out completely to get the product as a pale yellow liquid. Yield: 16.2 g.

Example 19:
Preparation of (+)-N,N-Dimethyl-1-phenyl-3-(1-naphthalenyl oxy)propanamine (+)-tartrate: Methanol (230 mL) and N,N-dimethyl-1-phenyl-3-(1-naphthalenyloxy) propanamine (100 g) are charged into round bottom flask at 28°C and stirred to obtain a clear solution. Charged the solution of L(+)-tartaric acid (49 g) in water (3000 mL) to the reaction mass at 28°C. The reaction mass is heated to 58°C and stirred for 15-20 minutes at the same temperature. The reaction mass is filtered to remove undissolved if any at 58°C. The filtrate is charged into round bottom flask and cooled to 28°C and cooled to 5°C and stirred for 25 minutes at 5°C. The precipitated solid is collected by filtration and washed with water (50 mL). The material is dried below 50°C. The material is charged into a round bottom flask and acetone (1725 mL) is added to the flask at 28°C. The reaction mass is heated to reflux and stirred for 20 minutes and further cooled to 20°C. The solid is collected by filtration and washed with acetone (100 mL). The same procedure for recrystallization is repeated twice and obtained material is dried below 50°C. Yield: 43 g.

Example 20:
Preparation of dapoxetine hydrochloride: (+)-N,N-Dimethyl-1-phenyl-3-(1-naphthalenyloxy)propanamine (+)-tartrate (170 g) and water (1500 mL) are charged into round bottom flask at 28°C. The reaction mass is further cooled to 20°C. The pH of the reaction mass is adjusted to 8 to 9 by adding 30 % sodium hydroxide solution at 20°C. Ethyl acetate (300 mL) is added to the reaction mass and stirred at 20°C. The layers are separated and aqueous layer is extracted with ethyl acetate (300 mL X2). The combined organic layer is washed with water and dried over sodium sulfate. The solvent is distilled off completely under vacuum to obtain dapoxetine as crude. Yield: 108 g;

Dapoxetine as obtained (108 g) and methyl tertiary butyl ether (1000 mL) are charged into a round bottom flask at 28°C and stirred to obtain a clear solution. The solution is cooled to 20°C and the solution of hydrogen chloride in methyl tertiary butyl ether (16 mL) is added dropwise at 20°C to adjust pH-2. The reaction mass is stirred for 15 minutes at the same temperature. The solid compound is isolated by filtration and washed with methyl tertiary butyl ether (20 mL X2). The material is dried under vacuum for 1 hour at the temperature below 50°C. The solid material and isopropyl alcohol are added to round bottom flask. The suspension was heated to dissolve and reflux for 15 minutes. The reaction mass is cooled to room temperature within 1 hour and further cooled to 10°C and stirred for 15 minutes. The solid compound is isolated by filtration and washed with isopropyl alcohol and hexane. The material is dried under vacuum at below 45°C. Yield: 105 g, chiral purity: 98.17%, HPLC purity: 99.85%

CLAIMS:

1. A process for preparing Dapoxetine hydrochloride comprising;

a) reducing 3-chloro-1-phenylpropan-1-one to provide (R)-3-chloro-1-phenylpropan-1-ol compound of Formula II;

Formula II

b) reacting the compound of Formula II obtained in step a) with 1-naphthol to provide the compound of Formula III;

Formula III

c) reacting the compound of Formula III obtained in step b) with methanesulfonyl chloride to provide the compound of Formula IV;

Formula IV

d) reacting the compound of Formula IV obtained in step c) with dimethylamine to provide dapoxetine compound of Formula V; and

Formula V

e) converting dapoxetine obtained in step d) to dapoxetine hydrochloride in presence of a source of hydrogen chloride.

2. A process according to claim 1, wherein reducing agent used in step a) is (+) Diisopinocampheylchloroborane [(+) DIP chloride].

3. A process according to claim 1, wherein the compound of Formula IV obtained in step c) is used in next step without isolation.

4. A process for preparing Dapoxetine hydrochloride comprising;

a) reacting methyl cinnamate with R-(+)-N-Benzyl-a-methylbenzylamine of Formula VI:

Formula VI to provide a compound of Formula VII;

Formula VII

b) debenzylating the compound of Formula VII obtained in step a) to provide a compound of Formula VIII;

Formula VIII

c) reducing the compound of Formula VIII obtained in step b) to provide a compound of Formula IX;

d) N-methylating the compound of Formula IX obtained in step c) to provide a compound of Formula X;

Formula X
e) reacting the compound of Formula X obtained in step d) with 1-fluoronaphthalene to provide dapoxetine; and

f) converting dapoxetine obtained in step e) to dapoxetine hydrochloride in presence of a source of hydrogen chloride.

5. A process according to claim 4, wherein debenzylation in step b) is carried out using palladium on charcoal in acetic acid under hydrogen pressure.

6. A process according to claim 4, wherein the reducing agent used in step c) is Vitride.

7. A process for preparing Dapoxetine hydrochloride comprising;

a) reducing D-phenylglycine followed by N-Boc protection or reducing N-Boc-D-phenylglycine to provide a compound of Formula XI;

Formula XI

b) reacting the compound of Formula XI obtained in step a) with methanesulfonyl chloride to provide a compound of Formula XII;

Formula XII

c) treating the compound of Formula XII obtained in step b) with sodium cyanide to provide a compound of Formula XIII;

Formula XIII

d) hydrolyzing the compound of Formula XIII obtained in step c) in presence of a base to provide a compound of Formula XIV;

Formula XIV

e) reducing the compound of Formula XIV obtained in step d) to provide a compound of Formula XV;

Formula XV

f) deprotecting the compound of Formula XV obtained in step e) using acid to produce a compound of Formula IX;

g) N-methylating the compound of Formula IX obtained in step f) to produce a compound of Formula X;

h) reacting the compound of Formula X obtained in step g) with 1-
fluoronaphthalene to provide dapoxetine; and i) converting dapoxetine obtained in step h) to dapoxetine hydrochloride in presence of a source of hydrogen chloride.

8. A process for preparing highly pure (+)-Dapoxetine or its pharmaceutically acceptable salts comprising;

a) resolving racemic dapoxetine with a chiral acid to obtain a chiral acid salt of (+)-dapoxetine;

b) converting the chiral acid salt of (+)-dapoxetine prepared in step (a) to (+)-dapoxetine and

c) converting the (+)-dapoxetine obtained in step b) into its pharmaceutically acceptable salts.

9. A process according to claim 8, wherein the chiral acid used in step a) for resolution is L (+)tartaric acid.

10. A pharmaceutical composition comprising Dapoxetine hydrochloride obtained according to any of the preceding claims and one or more pharmaceutically acceptable carrier.