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Title:
PROCESSES FOR THE PREPARATION OF (+)-N,N-DIMETHYL-2-[1-(NAPHTHALENYLOXY) ETHYL] BENZENE METHANAMINE AND INTERMEDIATES THEREOF
Document Type and Number:
WIPO Patent Application WO/2011/161690
Kind Code:
A1
Abstract:
The present invention relates to processes for the preparation of S(+)-N,N-dimethyl-2-[1-(naphthalenyloxy)ethyl]benzene methanamine and intermediates thereof. More particularly the present invention relates to preparation of the compound 3(S)-(+)-N,N-dimethylamino-3-phenyl propanol useful as intermediate in the synthesis of pharmaceutically active compounds.

Inventors:
MOHAN RAO, Dodda (8-2-293/82/A/202, D.No. 202Opp. Jubilee International Club,Road No. 14,Jubilee Hills, Hyderabad 3 Andhra Pradesh, 500 03, IN)
KRISHNA REDDY, Pingili (H.No. 13-1-183/1, Plot No. 69Snehapuri colony,Borabanda, Hyderabad 8 Andhra Pradesh, 500 01, IN)
JITHENDER, Aadepu (Velishala X Roads, ThirumalagiriNalgonda district,Nalgonda 3, Andhra Pradesh, 508 21, IN)
VENUGOPAL, Bingi (Post: Rampoor, Jammikunta RoadHuzurabad,Karimnagar District, Karimnagar 8 Andhra Pradesh, 505 46, IN)
Application Number:
IN2011/000116
Publication Date:
December 29, 2011
Filing Date:
February 25, 2011
Export Citation:
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Assignee:
SYMED LABS LIMITED (8-3-166/6&7, II FloorSree Arcade,Erragadda,Hyderabad 8, Andhra Pradesh, 500 01, IN)
MOHAN RAO, Dodda (8-2-293/82/A/202, D.No. 202Opp. Jubilee International Club,Road No. 14,Jubilee Hills, Hyderabad 3 Andhra Pradesh, 500 03, IN)
KRISHNA REDDY, Pingili (H.No. 13-1-183/1, Plot No. 69Snehapuri colony,Borabanda, Hyderabad 8 Andhra Pradesh, 500 01, IN)
JITHENDER, Aadepu (Velishala X Roads, ThirumalagiriNalgonda district,Nalgonda 3, Andhra Pradesh, 508 21, IN)
VENUGOPAL, Bingi (Post: Rampoor, Jammikunta RoadHuzurabad,Karimnagar District, Karimnagar 8 Andhra Pradesh, 505 46, IN)
International Classes:
A01N37/00; A61K31/20
Attorney, Agent or Firm:
KRISHNA REDDY, Pingili (8-3-166/6&7, II FloorSree Arcade,Erragadda,Hyderabad 8, Andhra Pradesh, 500 01, IN)
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Claims:
We Claim:

1) A process for preparing the intermediate compound of formula (Ilia),

(Ilia)

Where Rl and R2 are independently H or methyl

comprising:

reacting the compound of formula (Illb) or a salt thereof

(Illb)

Where Rl, R2 are independently H or methyl and R3 is H or Ci-C8 alkyl straight chain or branched or aryl alkyl

with a suitable reducing agent optionally in the presence of an acid and an organic solvent.

2) The process of claim 1 , wherein the suitable reducing agent is selected from the group consisting of sodium borohydride, lithium aluminum hydride, vitride or mixture thereof, preferably sodium borohydride in the presence of an acid.

3) The process of claim 1, wherein the acid is selected from the group consisting of organic acid like phosphonic acid, para toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid, formic acid, maleic acid, acetic acid, succinic acid, citric acid, oxalic acid, benzoic acid, ascorbic acid, inorganic acid like hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or their aqueous mixtures thereof, preferably methane sulfonic acid.

4) The process of claim 1 , wherein the organic solvent used is selected from the group

consisting of ethers like tetrahydrofuran, 1,4-dioxane, hydrocarbons like toluene, xylene, cyclohexane, aprotic polar solvents like Ν,Ν-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide, N-methyl pyrolidone (NMP) or mixtures thereof, preferably tetrahydrofuran or dimethyl sulfoxide.

5) The process of claim 6, wherein the reaction is carried out at temperatures from about 25°C to about 100°C, preferably from about 25°C to about 50°C.and the time period is from about 1 hour to about 48 hours, preferably from about 1 hour to 10 hours.

6) A process for preparing the intermediate compound of formula (Ila),

Ila

Where Ri, R2 are independently H or methyl

comprising:

reacting the compound of formula (lib) or a salt

(lib)

Where Ri, R2 are independently H or methyl and R3 is H or Q-Q alkyl straight chain or branched or aryl alkyl

with a suitable reducing agent optionally in the presence of an acid and an organic solvent.

7) The process of claim 6, wherein the suitable reducing agent is selected from the group consisting of sodium borohydride, lithium aluminum hydride, vitride or mixture thereof, preferably sodium borohydride in the presence of an acid.

8) The process of claim 6, wherein the acid is selected from the group consisting of organic acid like phosphonic acid, para toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid, formic acid, maleic acid, acetic acid, succinic acid, inorganic acid like hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or their aqueous mixtures thereof, preferably methane sulfonic acid.

9) The process of claim 7, wherein the organic solvent used is selected from the group consisting of ethers like tetrahydrofuran, 1,4-dioxane, hydrocarbons like toluene, xylene, cyclohexane, aprotic polar solvents like Ν,Ν-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide, N-methyl pyrolidone (NMP) or mixtures thereof, preferably tetrahydrofuran or dimethyl sulfoxide.

10) The process of claim 6, wherein the reaction is carried out at temperatures from about 25°C to about 100°C, preferably from about 25°C to about 50°C.and the time period is from about 1 hour to about 50 hours, preferably from about 1 hour to 10 hours.

1 1) A process for preparing the intermediate compound 3(S)-(+)-N,N-dimethylamino-3- phenyl propanol of formula (V),

(V)

comprising:

a) reacting the compound 3-N,N-dimeth lamino-3-phenyl propanol of formula (III)

(III)

with a suitable resolving agent in the presence of an organic solvent to form a diastereomeric mixture,

b) separating the compound of formula IV) from the diastereomeric mixture formed in step a),

(IV)

where X is a chiral acid or derivative thereof

c) reacting the compound of formula (IV) with a base in the presence of an organic solvent to form a compound of formula (V). 12) A process of claim 1 1 , wherein the chiral acid is selected from the group consisting of L(+) mandelic acid, L(+) tartaric acid, diisopropyl D-tartaric acid, di-p-toluyl D(+) tartaric acid, Diethyl- D(+)-tartrate, (+)-Dibenzoyl-D-tartaric acid, 2-chloromandelic acid, camphor sulfonic acid or their enantiomers or mixtures thereof, preferably (+)-Dibenzoyl -D-tartaric acid or L(+)tartaric acid.

13) A process of claim 1 1, wherein organic solvent employed in step a) is selected form the group consisting of water, alcohols like methanol, ethanol, propanol, isopropanol, butanol, esters like ethyl acetate, methyl acetate, n-butyl acetate, ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone or mixtures thereof, preferably ethyl acetate or ethanol. 14) A process of claim 1 1 , wherein reaction step a) is carried out at temperatures from about 25°C to about boiling point of the solvents used. Preferably at boiling point of the solvent used.

15) A process of claim 1 1, wherein the base used in step c) is selected from the group

consisting of organic bases like triethylamine, tripropylamine, pyridine, diisopropylamine, diisopropylethylamine, Inorganic bases like sodium hydroxide, potassium hydroxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogen

carbonate, ammonia or mixtures thereof, preferably sodium hydroxide or ammonia.

16) A process of claim 1 1, wherein the organic solvent used in step c) is selected from the group like hydrocarbons like n-hexane, n-heptane, toluene, xylene, halogenated solvents like methylene chloride, ethylene chloride, trichloroethylene, chloroform, dichlorobenzene, esters like ethyl acetate, isopropyl acetate or mixtures of thereof. Preferably methylene chloride.

17) A process of claim 1 1, wherein the reaction step c) is carried out at temperatures from about 25 °C to about 50°C, preferably about 30°C.

18) A compound having the structural formula (IV)

Where X is chiral acid or derivative thereof, preferably (+)-Dibenzoyl-D-tartaric acid or L(+) tartaric acid. 19) A process for the racemisation for the conversion of (+) or (-) -N,N-dimethylamino-3- phenyl propanol (V) into the racemic compound of formula III

comprising:

a) reacting 3(S)-(+)-N,N-dimethylamino-3-phenyl propanol compound of

formula (V) with a base optionally in the presence of a solvent; and

b) recovering the racemic mixture compound of formula (III) in pure form.

20) A process of claim 19, wherein the base used is selected from the group consisting of organic base like triethylamine, tripropylamine, pyridine, diisopropylamine,

diisopropylethylamine, Inorganic bases like sodium hydroxide, potassium hydroxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, ammonia or mixtures thereof, preferably potassium tertiary butoxide or potassium hydroxide.

21) A process of claim 19, wherein the organic solvent optionally used is selected from the group like hydrocarbons like n-hexane, n-heptane, toluene, xylene, halogenated solvents like methylene chloride, ethylene dichloride, chloroform, dichlorobenzene, esters like ethyl acetate, isopropyl acetate, aprotic polar solvents such as dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile or mixtures thereof, preferably dimethyl sulfoxide (DMSO).

22) A process of claim 19, wherein the reaction is carried out from about 30°C to about 100°C, or boiling point of the solvents used, preferably about 90°C.

23) The process of claim 19, wherein acid used in step b) is selected from the group consisting of organic acid like phosphonic acid, sulfonic acid, methane sulfonic acid, benzene sulfonic acid, formic acid, maleic acid, acetic acid, succinic acid, citric acid, oxalic acid, benzoic acid, ascorbic acid, inorganic acid like hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or their aqueous mixtures thereof, preferably hydrochloric acid.

24) The process of claim 19, wherein the organic solvent used in step b) is selected from

halogenated solvents like dichloromethane, ethylene dichloride , chloroform, esters like ethyl acetate, isopropyl acetate, hydrocarbons like toluene, xylene, n-hexane, n-heptane, cyclohexane or mixtures thereof, preferably, ethyl acetate.

25) A process for the preparing S(+)-N,N-dimethyl-2-[l-(naphthalenyloxy)ethyl]benzene methanamine of formula (la) or a pharmaceuticall acceptable salt thereof

(la)

comprising :

reacting the compound S(+)-3-N,N-dimeth lamino-3-phenyl propanol of formula V

V

with the compound naphthalene derivative of formula VII

VII

Where X is a leaving group like halogen (CI, Br, F, I) S03H,

in the presence of suitable base and an organic solvent.

26) The process of claim 25, wherein the base is selected from the group consisting of

inorganic bases like sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, organic bases like triethylamine, tripropylamine, pyridine, dimethyl amino pyridine,

diisopropylamine, diisopropylethyl-amine and the like, preferably triethylamine or mixtures thereof, preferably potassium carbonate or sodium hydroxide.

27) The process of claim 25, wherein the solvent is selected from the group consisting

of water, alcohols like methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butyl alcohol, ketones like acetone, methyl isobutyl ketone, ethers like

tetrahydrofuran, 2-methyl tetrahydrofuran, aprotic polar solvents like N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide, N-methyl pyrolidone (NMP) or mixtures thereof, preferably dimethyl sulfoxide or tetrahydrofuran or 2-methyl tetrahydrofuran.

28) The process of claim 25, wherein the reaction is carried out from about 25°C to about 100°C or boiling point of the solvents used, preferably from about 0°C to about 100 °C and the time period is from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours. 5 29) Dapoxetine or a salt thereof preferably hydrochloride of claim 29, has enantiomeric purity greater than about 99.0% as measured by chiral HPLC.

30) Dapoxetine or a salt thereof preferably hydrochloride of claim 29, having the individual impurities lower than about 0.15 area %, and total impurities lower than about 0.5 area% by HPLC.

10 31) Dapoxetine or a pharmaceutically acceptable salt thereof having the compound 3-amino-3- phenyl propanol of formula (lb)

(lb)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

15 32) Dapoxetine or a pharmaceutically acceptable salt thereof having the compound 3-N,N- dimethylamino-3-phenyl propanol of formula III)

(III)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

33) Dapoxetine or a pharmaceutically acceptable salt thereof having the compound (S)-(+)-3 N,N-dimethylamino-3-phenyl pro anol of formula (V)

(V)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

34) Dapoxetine or a pharmaceutically acceptable salt thereof having the compound (+)

2,3-Dibenzoyl-D-tartaric acid of formula (VIII)

(VIII)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

35) Dapoxetine or a pharmaceutically acceptable salt thereof having the compound

naphthalene derivative of formula (VI

(VII)

Where X is a leaving group like halogen (CI, Br, F, I) S03H etc.

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

36) Dapoxetine or a pharmaceutically acceptable salt thereof having the compound 1-naphthol of formula (Vila)

(Vila)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

37) Dapoxetine or a pharmaceutically acceptable salt thereof having the compound N

desmethyl dapoxetine of formula IX)

(IX)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

38) Dapoxetine or a pharmaceutically acceptable salt thereof having the compound N,N

didesmethyl dapoxetine of formula (IXa)

(IXa)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

39) Dapoxetine or a pharmaceutically acceptable salt thereof having the compound (-)-Ν,Ν- dimethyl-l-phenyl-3-(l-naphthalenyloxy)propanamine (R-(-)-Dapoxetine) of formula (IXb)

(IXb)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

Description:
PROCESSES FOR THE PREPARATION OF (+)-N,N- DIMETHYL-2-[l-(NAPHTHALENYLOXY) ETHYL] BENZENE METHAN AMINE

AND INTERMEDIATES THEREOF

PRIORITY

This application claims the benefit of Indian Provisional Applications with no.l770/CHE/2010, filed on 23 June 2010 and 108/CHE/201 1 filed on 13 January 201 1, the contents of each of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to processes for the preparation of S(+)-N,N-dimethyl-2- [l-(naphthalenyloxy)ethyl]benzene methanamine and intermediates thereof.

2. Description of the Related Art

Dapoxetine hydrochloride is the potent selective serotonin reuptake inhibitors (SSRIs) the most advanced agent under review in US and approved in some of the european countries for premature ejaculation. Dapoxetine is structurally related to the antidepressant fluoxetine (Prozac) is enantiomerically pure and one of the important drug as a serotonin reuptake inhibitor. Dapoxetine hydrochloride is available under the brand name PRILIGY™ in Europe. Dapoxetine hydrochloride is chemically known as S(+)-N,N-dimethyl-2-[l-(naphthalenyloxy)- ethyl]benzene methanamine hydrochloride (here after referred by its generic name dapoxetine) and represented by the formula (I).

(I) U.S. Patent No. US 5,135,947 describes l-phenyl-3-napthalenyloxypropanamines including dapoxetine or pharmaceutically acceptable acid addition salts thereof, a pharmaceutical composition and a method of treatment.

The US '947 patent discloses a process for the preparation of dapoxetine and its salts which is illustrated by scheme below:

Conversion of 3-amino-3-phenylpropanoic acid (II) into 3-amino-3-phenyl propanol (lb) by reduction process using sodium borohydride in the presence of an acid had not been reported. Resolution of 3-N,N-dimethylamino-3-phenylpropanol (III) into optically pure 3(S)- (+)-N,N-dimethylamino-3-phenylpropanol (V) using chiral acids i.e., by classical method is not known.

As of now the reduction process for the preparation of compounds of formula (Ilia) and

(Ila) by using sodium borohydride in the presence of an acid is not known.

The conversion of compound of formula III to the optically pure compound of formula V by resolution using chiral acid and additional acid is not reported.

The reported process for the preparation of compound of formula (la) by condensation of compound of formula V with compound of formula VII uses sodium hydride which is hazardous and difficult to handle on industrial scale. Whereas the process of present invention uses mild and simple base sodium hydroxide which is cheaper and easy to handle on commercial scale.

The processes reported for the preparation of Dapoxetine involves resolution of the final compound which has disadvantages like racemisation and recycle of the wanted isomer is not possible leading to poor yields and purities of the final product.

Whereas the processes of present invention has advantages as they uses optical pure intermediates for the preparation of dapoxetine and the unwanted isomers can be racemised and the wanted isomers can be recycled thus giving the final compounds with high yield and purities and most cost effective, industrially applicable.

The process of the invention makes it possible to obtain the target enantiomer of the compound of formula (la) in an excellent enantiomeric excess, with high productivity and in an excellent yield.

The processes reported in the prior art are expensive; difficult to handle on commercial scale, requires additional purification steps intermittently thus ending up with low yields and purities of the final product thus rendering the process not viable on commercial scale. Hence there is a need in the art for an improved process for the preparation of dapoxetine and its intermediates, which avoids the use of potentially hazardous chemicals, the likely formation of isomeric and other process related impurities, while enhancing the desired product dapoxetine or a pharmaceutically acceptable salt resulting in higher yield and purity. The simple, eco-friendly, inexpensive, reproducible, robust processes, herein described for the preparation of intermediates of dapoxetine are well suited on an industrial scale.

SUMMARY OF THE INVENTION

The present invention relates to processes for the preparation of S(+)-N,N-dimethyl-2- [l-(naphthalenyloxy)ethyl]benzene methanamine and intermediates thereof.

In one aspect, the present invention relates to a process for preparing the intermediate compound of formula (Ilia),

(Ilia)

Where Rl and R2 are independently H or methyl

comprising:

reacting the compound of formula (Illb) or a salt thereof

(Illb)

Where Rl, R2 are independently H or methyl and R 3 is H or Ci-Cg alkyl straight chain or branched, aryl alkyl.

with a suitable reducing agent.

In another aspect, the present invention relates to a process for preparing the intermediate compound of formula (Ha),

(Ila)

Where Rl, R2, are independently H or methyl

comprising: reacting the compound of formula (lib) or a salt thereof

Where Rl, R2, are independently H or methyl and R 3 is H or Ci-C 8 alkyl straight chain or branched, aryl alkyl.

with a suitable reducing agent.

In yet another aspect, the present invention relates to a process for preparing the intermediate compound 3(S)-(+)-N,N-dimeth lamino-3-phenyl propanol of formula (V),

(V)

comprising:

a) reacting the compound 3-N,N-dimethylamino-3- henyl propanol of formula (III)

(HI)

with a suitable resolving agent, in the presence of an organic solvent to form a diastereomeric mixture and

b) separating the compound of formula (IV) from the diastereomeric mixture formed in step a),

(IV) where X is a chiral acid or a derivative thereof,

c) reacting the compound of formula (IV) with a base in the presence of an organic solvent to form a compound of formula (V).

In yet another aspect, the present invention rovides the compound of formula (IV)

(IV)

Where X is chiral acid or derivative thereof, preferably (+)-Dibenzoyl-D-tartaric acid or L-(+) tartaric acid

In yet further aspect, the present invention relates to racemisation process for the conversion of (+) or (-) 3-N,N-dimethylamino-3-phenyl propanol into the racemic compound of formula III comprising :

a) reacting 3(S)-(+)-N,N-dimethylamino-3-phenyl propanol compound of formula (V) with a base ; and,

b) recovering the racemic mixture compound of formula (III) in pure form.

In yet another aspect, the present invention relates to a process for the preparation f S

(+)-N,N-dimethyl-2-[l-(naphthalenyloxy)ethyl]benzene methanamine of formula (la) or a pharmaceutically acceptable salt thereof

(la)

comprising :

a) reacting the compound S(+)-3-N,N-dimeth lamino-3-phenyl propanol of formula V

V

with the compound naphthalene derivative of formula VII

VII

Where X is a leaving group like halogen (CI, Br, F, I), S0 3 H, etc

in the presence of suitable base and an organic solvent.

In another aspect, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound 3-amino-3-phenyl propanol of formula (lb)

in an amount less than or equal to 0.10 area %, as measured by HPLC.

In another aspect, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound 3-N,N-dimethylamino-3-phenyl propanol of formula (III)

(III) in an amount less than or equal to 0.10 area % as measured by HPLC.

In another aspect, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (S)-(+)-3-N,N-dimethylamino-3-phenyl propanol of formula (V)

(V)

in an amount less than or equal to 0.10 area % as measured by HPLC. In another aspect, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (+)-2,3-Dibenzoyl-D-tartaric acid of formula (VIII)

(VIII) in an amount less than or equal to 0.10 area % as measured by HPLC.

In another aspect, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound naphthalene derivative of formula (VII)

(VII)

Where X is a leaving group like halogen (CI, Br, F, I), S0 3 H,

in an amount less than or equal to 0.10 area % as measured by HPLC.

In another aspect, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound 1-naphthol of formula (Vila)

(Vila) in an amount less than or equal to 0.10 area % as measured by HPLC.

In another aspect, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound N-desmethyl dapoxetine of formula (IX)

. (IX) '

in an amount less than or equal to 0.10 area % as measured by HPLC. In another aspect, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound Ν,Ν-didesmethyl dapoxetine of formula (IXa)

(IXa) in an amount less than or equal to 0.10 area % as measured by HPLC.

In another aspect, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (-)-N,N-dimethyl-l-phenyl-3-(l- naphthalenyloxy)propanamine (R-(- -Dapoxetine) of formula (IXb)

(IXb) in an amount less than or equal to 0.10 area % as measured by HPLC.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to processes for the preparation of S(+)-N,N-dimethyl-2- [l-(naphthalenyloxy)ethyl]benzene methanamine and intermediates thereof.

In one embodiment, the present invention provides a process for preparing the intermediate compound of formula (Ilia),

(Ilia)

Where Rl and R2 are independently H or, methyl

comprising:

reacting the compound of formula (Illb) or a salt thereof

(Illb)

Where Rl, R2 are independently H or methyl and R 3 is H or Ci-C 8 alkyl straight chain or branched, aryl alkyl.

with a suitable reducing agent optionally in the presence of an acid and an organic solvent.

The suitable reducing agent that can be used is selected from the group consisting of sodium borohydride, lithium aluminum hydride, vitride and the like; preferably sodium borohydride in the presence of an acid is being used.

The acid that can be used include but are not limited to organic acid or inorganic acid. Organic acids such as phosphonic acid, para toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid, formic acid, maleic acid, acetic acid, succinic acid, and the like; Inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid; sulfuric acid, phosphoric acid and the like, and their aqueous mixtures thereof, preferably methane sulfonic acid is being used.

The molar equivalents of acid and the reducing agent used can be from about 0.5 to about 5 moles on the weight of the starting compound Illb taken.

The organic solvent that can be used is selected from the group consisting of ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; aprotic polar solvents such as Ν,Ν-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide, N-methyl pyrolidone (NMP) or mixtures thereof. Preferably tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO) is being used.

The reaction temperature and time should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products. The reaction is carried out at temperature from about 25°C to about 100°C or boiling point of the solvents used. Preferably from about 25°C to about 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 reagent and solvent(s) employed. The time period is from about 1 hour to about 45 hours, preferably from about 1 hour to fO hours. In another embodiment, the present invention provides a process for preparing the intermediate compound of formula (Ila),

Ila

Where Rl , R2 are independently H or methyl

comprising:

reacting the compound of formula (lib) or a salt thereof,

(lib)

Where Rl, R2 are independently H or methyl and R 3 is H or C)-C 8 alkyl straight chain or branched, aryl alkyl.

with a suitable reducing agent optionally in the presence of an acid and an organic solvent.

The suitable reducing agent, acid, organic solvent and reaction temperature, time are same as applicable as mentioned in the above embodiment.

In yet another embodiment of the present invention, there is provided a process for preparing the intermediate compound 3(S)-(+)-N,N-dimethylamino-3-phenyl propanol of formula (V),

(V)

comprising:

a) reacting the compound 3-N,N-dimethylamino-3-phenyl propanol of formula (III)

(III)

with a suitable resolving agent in the presence of an organic solvent to form a diastereomeric mixture,

b) separating the compound of formula (IV) from the diastereomeric mixture formed in step a),

(IV)

where X is a chiral acid or a derivative thereof.

c) reacting the compound of formula (IV) with a base, in the presence of an organic solvent to form a compound of formula (V).

The suitable resolving agent that can be used is selected from the group consisting of L(+) mandelic acid, L(+) tartaric acid, (+) di-p-toluyl D-tartaric acid, (+)-Dibenzoyl-D-tartaric acid, (+) diethyl D-tartrate, (+) diisopropyl D-tartrate, camphor sulfonic acid, 2- chloromandelic acid or their enantiomers and the like, preferably (+)-Dibenzoyl-D-tartaric acid or L(+) tartaric acid is being used.

The solvent that can be used in step a) include but are not limited to water, alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol and the like; ketones such as acetone, methylisobutylketone, methyl ethyl ketone and the like; esters such as ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate and the like; or mixtures of thereof. Preferably ethyl acetate or ethanol.

The reaction temperature can range from about 25 °C to about boiling point of the solvents used, preferably at boiling point of the solvents used.

The time period can be range from about 30 minutes to about 5 hours, preferably 1 hour. The solution obtained is optionally filtered through celite or diatamous earth to separate the extraneous matter present or formed in the solution by using conventional filtration technique known in the art.

The precipitation of solid is achieved but not limited to evaporation, cooling, drying, by adding antisolvent and the like. Preferably by cooling.

The temperature for the precipitation of solid can be from about -10 °C to about 30°C, preferably about 30°C.

The suitable base that can be used in step c) can include organic base or, inorganic base. Organic bases such as triethylamine, pyridine, diisopropylamine, diisopropylethylamine and the like; Inorganic bases such as ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like or mixtures thereof, preferably sodium hydroxide or ammonia is being used.

The organic solvent that can be used include but are not limited to hydrocarbons such as n-hexane, n-heptane, cyclohexane, toluene, xylene and the like; halogenated solvents such as methylene chloride, ethylene dichloride, chloroform, dichlorobenzene and the like; esters such as ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate and the like; or mixtures of thereof. Preferably methylene chloride is being used.

The reaction temperature can range from about 25 °C to about 40°C, preferably about

30°C.

The product obtained by the process described above can have high enantiomeric excess. Preferably, the amount of R-enantiomer is less than about 10% as measured. by area percentage HPLC, more preferably less than about 5%, and most preferably less than about 0.5%.

In yet another embodiment , the present invention provides the compound of formula IV

(IV)

Where X is chiral acid or derivative thereof, preferably (+)-Dibenzoyl-D-tartaric acid or L-(+) tartaric acid The compound of formula IV may be a crystalline or amorphous form or mixture thereof.

In yet another embodiment of the present invention, there is provided a racemisation process for the conversion of (+) or (-)-3-N, N-dimethylamino-3-phenyl propanol (V) into the racemic compound of formula III comprising:

a) reacting 3(S)-(+)-N,N-dimethylamino-3-phenyl propanol compound of formula (V) with a base optionally in the presence of a solvent(s) ; and

b) recovering the racemic mixture compound of formula (III) in pure form.

The base that can be used in step a) include organic base or inorganic base. Inorganic bases such as ammonia, sodium hydroxide, potassium hydroxide, potassium tertiary butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate and the like; Organic bases such as triethylamine, pyridine, diisopropylamine, diisopropylethylamine and the like or mixtures thereof. Preferably potassium tertiary butoxide or potassium hydroxide is being used.

The solvent that can be used optionally include but are not limited to hydrocarbons such as toluene, xylene, and the like; aprotic polar solvents such as dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), or mixtures thereof. Preferably dimethyl sulfoxide (DMSO) is being used.

The reaction temperature can range from about 30°C to about 100°C, or reflux temperature of the solvents used. Preferably about 90°C.

The pH of the reaction can be adjusted in step b) from about 0.1 to about 6, preferably

2.

The acid that can be used in step b) include but are not limited to inorganic acid that can be used include, but are not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and their aqueous mixtures thereof, preferably hydrochloric acid is being used.

The pH of the reaction in step c) can be adjusted from about 7 to about 12, preferably about 9.

The solvents that can be used for extraction of the product include, but are not limited to halogenated solvents such as dichloromethane, ethylene dichloride , chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbons such as toluene, xylene and the like; and mixtures thereof. Preferably dichloromethane is being used. In yet another embodiment, the present invention provides a process for the preparation of S(+)-N,N-dimethyl-2-[l-(naphthalenyloxy)ethyl]benzene methanamine of formula (la) or a pharmaceutically acceptable salt thereof .

Ia

comprising :

reacting the compound S(+)-3-N,N-dimeth lamino-3-phenyl propanol of formula V

II

with the compound naphthalene derivative of formula of VII

Where X is a leaving group like halogen (CI, Br, F, I) S0 3 H etc

in the presence of suitable base and an organic solvent.

The base that can be used include inorganic or organic base. Inorganic bases such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, ammonia and the like; and organic bases such as triethylamine, tripropylamine, pyridine, dimethyl amino pyridine, diisopropylamine, diisopropylethylamine and the like or mixtures thereof, preferably potassium carbonate or sodium hydroxide is being used.

The molar equivalent of base used can be from about 0.5 to about 10 on the weight of the compound of formula II taken. Preferably 5 molar equivalents. The solvents that can be used is selected from the group consisting of water, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran (THF), 2-methyl tetrahydrofuran and the like; aprotic polar solvents such as Ν,Ν-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), dimethyl acetamide, N-methyl pyrrolidone (NMP) or mixtures thereof. Preferably, dimethyl sulfoxide (DMSO) or tetrahydrofuran or 2-methyl tetrahydrofuran.

The reaction temperature and time should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products, the reaction temperature can be from about 25°C to about 100°C or boiling point of the solvents used. Preferably from about 50°C to about 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 reagent and solvent(s) employed. The time period is from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours.

After completion of the reaction, isolation of the desired compound from the reaction mixture can be carried out by common operation, but in consideration of the physical properties of the desired compound, crystallization, extraction, washing, column chromatography, etc. can be combined.

The intermediate compounds can be optionally purified by recrystallisation, using a solvent or mixture of solvents; or by converting into their corresponding pharmaceutically acceptable salts and then processed back to the original compounds.

The processes reported for the preparation of dapoxetine or a pharmaceutically acceptable salt thereof of formula (la) or its intermediates results in the formation of various impurities and bye products leading to include several purification steps thus resulting in very poor yields and purities of the final product.

Advantageously, the process of present invention provides the intermediates with higher yields and purities leading to higher yields and purities of final product.

Advantageously the processes of present invention provides substantially pure S- enantiomer that will be free from R-enantiomer as an impurity both in the precursor intermediate compounds used herein and also the final product dapoxetine or pharmaceutically acceptable salt thereof resulting in high yield greater than about 90% with chemical purity greater than 99.5% by HPLC and preferably greater than about 99.8% by chiral HPLC.

As referred above (+) dapoxetine is commonly called as dapoxetine thus can be referred here in either way.

In this specification the term "racemic mixture" may include mixtures of enantiomers in ratios other than, as well as, a 50:50 mixture of R:S enantiomers (for example from 99: 1 to 1 :99). A particular process of the invention begins with a 50:50 mixture of enantiomers. The process may involve differing mixtures of enantiomers at various stages (including, but not limited to 50:50 mixtures). The term "racemisation" covers the conversion of an unresolved enantiomer into a mixture containing the enantiomer to be resolved.

The processes reported in the literature for the preparation of dapoxetine or its intermediates results in several impurities and bye products leading to involve several purification steps thus resulting in very poor yields and purities of the final product.

Advantageously, the process of present invention provides the intermediates in higher yields and purities which further results in higher yields and purities of final product.

As referred above (+) dapoxetine is commonly called as dapoxetine thus can be referred here in either way.

In another embodiment, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound 3 -amino-3 -phenyl propanol of formula (lb)

(lb)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

In yet another embodiment, the present invention provides dapoxetine or pharmaceutically acceptable salt thereof having the compound 3-N,N-dimethylamino-3-phen propanol of formula (III)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

In yet further embodiment, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (S)-(+)-3-N,N-dimethylamino- 3-phenyl propanol of formula (V)

(V)

in an amount less than or equal to 0.10 area percent, as measured by HPLC. In another embodiment, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (+)-2,3-Dibenzoyl-D-tartaric acid of formula (VIII) (VIII)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

In another embodiment, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound naphthalene derivative of formula (VII)

(VII)

Where X is a leaving group like halogen (CI, Br, F, I), S0 3 H etc.

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

In yet another embodiment, the present invention provides dapoxetine or pharmaceutically acceptable salt thereof having the compound 1-naphthol of formula (Vila)

(Vila) in an amount less than or equal to 0.10 area percent, as measured by HPLC.

In another embodiment, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound N-desmethyl dapoxetine of formula (IX)

(IX) in an amount less than or equal to 0.10 area percent, as measured by HPLC.

In another embodiment, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound Ν,Ν-didesmethyl dapoxetine of formula (IXa)

(IXa)

amount less than or equal to 0.10 area percent, as measured by HPLC.

In another embodiment, the present invention provides dapoxetine or a pharmaceutically acceptable salt thereof having the compound (-)-N,N-dimethyl-l-phenyl-3- (l-naphthalenyloxy)propanamine (R-(-)-Dapoxetine) of formula (IXb)

(IXb)

in an amount less than or equal to 0.10 area percent, as measured by HPLC.

The crystal particles of dapoxetine or a pharmaceutically acceptable salt preferably hydrochloride obtained by the by the processes of present invention has a mean particle size less than about 500 μηι, more preferably less than about 200 μηι, most preferably less than about 100 μιη. The present invention provides dapoxetine hydrochloride particles obtained by the processes described above having a mean particle size ranging from about 5 μπι to about 200 μιη. As used herein, the term "μπι" refers to "micrometer" which is lxl0~ 6 meter. As used herein, "crystalline particles" means any combination of single crystals, aggregates and agglomerates. As used herein, the phrase "mean particle size distribution, i.e., d (0.5)" means the median of said particle size distribution.

In yet another embodiment, dapoxetine or its pharmaceutically acceptable salts obtained by the process described above has residual organic solvents or organic volatile impurities comprises less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; less than about 2000 ppm of methanol, ethanol, tetrahydrofuran (THF), ethyl acetate, dimethyl sulfoxide (DMSO) and less than about 500ppm of dichloromethane, toluene.

The present invention provides simple, ecofriendly, inexpensive, reproducible, robust processes for preparation intermediates of dapoxetine, which forthwith are viably adaptable on a commercial scale.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. EXAMPLES

Example -1: Preparation of 3-amino-3-phenyl propanol

50 grams of 3-amino-3-phenyl propanoic acid was suspended in 75 ml of dimethylsulfoxide (DMSO) and stirred for about 10 mins.28 grams of sodium borohydride was added portion wise. After completion of addition, the resultant reaction mixture was stirred for about 1 to 2hrs.A mixture of lOOgrams of methane sulfonic acid in 75 ml of dimethyl sulfoxide (DMSO) was added and stirred at about 30°C until the reaction completion as monitored by GC. The reaction mixture was quenched with water and basified to about pH 9-10 with sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and distilled completely to afford the residue.

Residue wt: 47.5gms.

Purification: The residue obtained above was dissolved in water followed by adjusting the pH to about 2 with cone, hydrochloric acid. The pH of aqueous layer was adjusted to about 9 with sodium hydroxide solution. The aqueous layer was extracted with Ethyl acetate and distilled at about 55°C under vacuum and reef ystal Used in a mixture of diisoproyl ether, butyl acetate and methanol to afford of the title compound as white solid.

Solid wt: 41gms. (% Yield: 89.6%); Purity by HPLC: 92.5%.

Example-2: Preparation of 3(S)-(+)-N,N-dimethyI amino-3-phenyl propanol

500ml of ethyl acetate and 51 grams of (+)-Dibenzoyl-D-tartaric acid (DBTA)were charged in a clean and dry 1 lit. 4 neck RBFlask and stirred for about 10 mins. The resultant reaction solution was filtered on celite to make homogenous solution. To the filtrate 30 grams of 3-N,N- dimethylamino-3-phenyl propanol dissolved in 120 ml of ethanol was added at about 30°C followed by stirring for about 30 mins. Solid separation was observed. The reaction mass was heated to reflux for about 30 mins. followed by cooling to about 25 °C. Separated solid was filtered and dried at about 35°C to afford (+) 3(S)-N,N-dimethylamino-3-phenyl propanol - Dibenzoyl D-tartarate.

Dry wt: 39 gms; SOR = (+) 86.4° ( 1% in CH 3 OH).

Recrystallization : 39 grams of (+) 3(S)-N,N-dimethylamino-3-phenyl propanol -Dibenzoyl D-tartarate, 78 ml of ethanol and 546 ml of water were taken and heated to reflux for about 20 minutes to make homogenous solution. The resultant solution was cooled to about 30°C. Separated solid was filtered and washed with 400ml of water to afford 28 gms of pure (+) 3(S)- N,N-dimethylamino-3-phenyl propanol -Dibenzoyl D-tartarate.

Dry wt.: 28gms; SOR: (+) 92.6° ( 1% in CH 3 OH).

14 gms of pure (+) 3(S)-N,N-dimethylamino-3-phenyl propanol -Dibenzoyl D- tartarate obtained in example 2 , 140ml of water and 150 ml of dichloromethane were charged in a clean and dry 500ml 4 neck RBFlask and stirred for about 10 mins The resultant reaction solution was basified to a pH of about 9 by adding 10% caustic lye solution followed by stirring for about 30 mins. Organic and aqueous layers were separated and the aqueous layer was extracted with 3x 100ml of dichloromethane. The total organic layer was

washed with 5x150 ml of water. The total organic layer was separated and distilled at about 30°C under vacuum to afford 4.5 gms of title compound.

Residue wt: 4.5gr (%Yield:60% );SOR : (+) 42.68° ( 0.6% in CHC1 3 ); Purity by HPLC: 99.1% Example -3: Racemisation process of (+) or (-)-3N, N-dimethyl amino-3- phenyl propanol intermediate

25ml of dimethyl sulfoxide and 2 gms of (+)- or (-)-3-N,N-dimethylamino-3-phenyl propanol and 5 gms of potassium tertiary butoxide were charged in a clean and dry 250 ml 4 neck RBF followed by heating to about 90°C. The resultant reaction mixture was stirred at about 90°C for about 3 hours. The reaction mixture was cooled to about 35°C and was quenched by adding reaction mixture into 100ml of water at about 30°C. The aqueous layer was acidified to about p H 1 with cone, hydrochloric acid followed by washing with 3x100ml of toluene. The aqueous layer was basified to a pH of about 9 with 10% caustic lye solution followed by extraction with 3x150 ml of ethyl acetate. Organic and aqueous layers were separated and the organic layer was distilled completely at about 55°C under vacuum to afford racemic mixture 3-N,N-dimethyl-amino-3-phenyl propanol.

Wt: 1.5gr. (% Yield: 75% ); SOR : (+) 0.607° ( 0.6% in CH 3 OH); Purity by HPLC: 95%.

Example -4: Preparation of 3-Amino-3-phenyl propanol

Same procedure as described in Ex 1 but using tetrahydrofuran (THF) (750ml) instead of dimethyl sulfoxide (DMSO) to provide the title compound.

Wt: 46 gms.(% Yield: 96.34%); Purity by HPLC: 96%. Example -5: Preparation of (-)-3-Amino-3-phenyl propanol

Same procedure as described in Ex 1 but using (-)-3-amino-3-phenyl propanoic acid instead of racemic 3-amino-3-phenyl propanoic acid and tetrahydrofuran (THF) (750ml) in place of dimethyl sulfoxide (DMSO) to provide the title compound.

Wt: 43gr. (%Yield: 90.05%); SOR: (-) 21.4°(0.5% in CHC1 3 ); Purity by HPLC: 95%.

Example-6: Preparation of (+)-Methyl-3-N, N-dimethyl amino-3-phenyl propanoate

7gr. of (-)-Methyl-3-amino-3-phenyl propanoate and 13.5ml. of formaldehyde solution (37-41% w/v) were charged in a clean and dry 500 ml 4 neck RB flask and heated to reflux temperature (95-100°C). 6.6ml. of formic acid was added drop wise over about 30 min. After complete of addition of formic acid, the reaction mass was stirred for 15min. at reflux temperature. The reaction was checked for completion, after completion, the reaction mass was cooled to ambient temperature and added 5ml. of Conc.hydrochloric acid. Then the reaction mass was washed with toluene (2x20ml).Aqueous layer was separated and cooled to 10- 15°C.Aqueous layer was basified with 20% sodium carbonate solution to a pH of 9-10. Organic layer was separated and 30ml. of chloroform was added. The total organic layer was washed with water (2x30ml.).Then chloroform layer was separated and distilled under vacuum to provide the title compound.

Wt: 5gr (%Yield: 62.5%); SOR: (+) 13-16°(1.46% CHC1 3 ); Purity by HPLC: 96%.

Example -7: Preparation of 3, N,N-dimethyl amino-3-phenyl propanol

Same procedure as described in Ex.1 by using 5 gms 3 -N,N-dimethyl amino-3-phenyl propanoic acid hydrochloride, 15 ml DMSO, 4 g. of sodium borohydride and 12.5 g. of methane sulfonic acid to provide the title compound.

Wt: 2gr. (%Yield: 51.4%); Purity by HPLC: 92%.

Example -8: Preparation of (+)-3, N,N-dimethyl amino-3-phenyl propanol

Same procedure as described in Ex 1 but using 5 g. of (+) -3-N,N-dimethyl amino-3- phenyl propanoic acid hydrochloride, 15 ml dimethyl sulfoxide (DMSO), 4 g. of sodium borohydride and 12.5 g. of methane sulfonic acid to provide the title compound.

Wt: 2gr. (%Yield: 51.4%); Purity by HPLC: 92%; SOR: + 44.2° (0.6% CHC1 3 ). Example -9: Preparation of (-)-3-Amino-3-phenyl propanol

Same procedure as described in Ex. 1 but using 20 g. of (-)-3-amino-3-phenyl propanoic acid hydrochloride, 60 ml of DMSO, 18 g. of sodium borohydride and 76 g. of methane sulfonic acid to provide the title compound.

Wt: 1 lgr. (%Yield: 73.4%); SOR : (-) 21.8° (0.5% in CHC1 3 ); Purity by HPLC: 92.5%.

Example -10: Preparation of 3-Amino-3-phenyl propanol

Same procedure as described in Ex. 1 but using 20 gms of 3-amino-3-phenyl propanoic acid hydrochloride, 60ml of dimethyl sulfoxide (DMSO), 18 g. of sodium borohydride and 76 g. of methane sulfonic acid to provide the title compound.

Yield: 1 lgr. (%Yield: 73.4%); Purity by HPLC: 92.8%.

Example -11: Preparation of (-)-3-Amino-3-phenyl propanol

Same procedure as described in Ex. 1 but using 5 g. of (-)-methyl-3-amino-3-phenyl propanoate, 15 ml of DMSO, 2.6 g. of sodium borohydride and 10 g. of methane sulfonic acid to provide the title compound.

Yield: 2gr (%Yield: 47.61%); SOR : -21.389°(0.5% CHC1 3 ); Purity by HPLC: 93.4%.

Example -12: Preparation of 3-Amino-3-phenyl propanol

Same procedure as described in Ex. 1 but using 5 g. of methyl-3-amino-3-phenyl propanoate, 15 ml of DMSO, 2.6 g. of sodium borohydride and 10 g. of methane sulfonic acid to provide the title compound.

Yield: 2gr.(% Yield: 47.6%); Purity by HPLC: 93%.

Example -13: Preparation of (+)-Methyl-3-N,N-dimethylamino-3-phenyl propanoate

Step-a: 190gr. of (+)-p-ditoluyl tartaric acid and 400ml. of ethyl acetate were charged into a clean and dry 1 lit. 4 neck RB Flask and stirred for about 15min. l00gr. of methyl-3-Ν,Ν- dimethylamino-3-phenyl propanoate was added and stirred for about lOmin.Then the resulted solution was heated to reflux and maintained for about Ihr. The resultant reaction mass was cooled to about 30°C and stirred for about Ihr. The reaction mass was filtered to obtain the of (+)-methyl-3-N,N-dimethylamino-3-phenyl propanoate p-ditoluyl tartaric acid salt.

Dry wt: 250gr.; SOR = +88.276° (1% CH 3 OH). Recrystallization of p-ditoluyl tartaric acid salt of (+)-methyl-3-N,N-dimethylamino-3- phenyl propanoate:

20gr. of (+)-methyl-3-N,N-dimethylamino-3-phenyl propanoate p-ditoluyl tartarate salt and 530ml. of ethyl acetate were charged into a clean and dry 500ml 4 neck RB Flask and heated to reflux. The reaction mass was maintained under reflux for about 5hrs. The reaction mixture was cooled to about 30 °C and further cooled to about 0°C followed by -10° to - 5°C.The reaction mass stirred for 2-2 l/2hrs. at -10° to -5°C and filtered at the same temperature to provide the pure (+)-methyl-3-N,N-dimethylamino-3-phenyl propanoate p- ditoluyl tartarate salt. Dry wt: 2.5gr.

Step-b; 2.5 gr. of pure (+)-methyl-3-N,N-dimethylamino-3-phenyl propionate p-ditoluyl tartarate salt, 30ml. of water and 20ml. of 20%w/v sodium carbonate solution were charged into a clean and dry 250 ml. 4 neck RB Flask and stirred for about 5 min.Then extracted with dichloromethane (2 x 80ml). The organic layers were combined and washed with 80ml. of water. The organic layer was separated and treated with 0.5gr. of charcoal carbon and distilled completely under vacuum to provide the title compound.

Residue wt: 0.5gr.(% Yield: 12.5%);SOR:(+) 11.788°( 1%CHC13); Purity by HPLC: 98.5%. Example -14: Preparation of 3-N,N-dimethyl amino-3-phenyl propanol

Same procedure as described in Ex. 1 but using 50 g. of 3-N,N-dimethyl aminos- phenyl propanoic acid, 750 ml of tetrahydrofuran (THF), 24.5 g. of sodium borohydride and 64 g. of methane sulfonic acid to provide the title compound.

Wt: 40-42gr. (%Yield: 90.7%); Purity by HPLC: 98%.

Example-15: Preparation of (+)-3-N,N-dimethyl amino-3-phenyI propanol

Same procedure as described in Ex. 1 but using 50 g. of (+)-3-N,N-dimethyl amino-3- phenyl propanoic acid, 750 ml of tetrahydrofuran (THF), 24.5 g. of sodium borohydride and 64 g. of methane sulfonic acid to provide the title compound.

Wt: 40-42gr. (%Yield: 90.7%); Purity by HPLC: 98%; SOR: +44.4° (0.6% CHCI3).

Example-16: Preparation of 3-N,N-dimethyl amino-3-phenyl propanol Same procedure as described in Ex. 1 but using 50 g. of 3-N,N-dimethyl amino-3- phenyl propanoic acid hydrochloride, 750 ml of tetrahydrofuran (THF), 24.6 g. of sodium borohydride and 87.08 g. of methane sulfonic acid to provide the title compound to provide the title compound. Wt: 30-32gr. (%Yield: 82.26%); Purity by HPLC: 96%.

Example -17: Preparation of (+)-3-N,N-dimethyl amino-3-phenyl propanol

Same procedure as described in Ex. 1 but using 50 g. of (+)-3-N,N-dimethyl amino-3- phenyl propanoic acid hydrochloride, 750 ml of tetrahydrofuran (THF), 24.6 g. of sodium borohydride and 87.08 g. of methane sulfonic acid to provide the title compound.

Wt: 30-32gr. (%Yield: 82.26%); SOR : (+) 43.56°(0.6% in CHC1 3 ); Purity by HPLC: 98%. Example-18: Preparation of 3-N,N-dimethyl 3-phenyl propanol

Same procedure as described in Ex. 1 but using 30 g. of 3-N,N-dimethyl amino-3- phenyl propanoic acid, 640 ml of tetrahydrofuran (THF), 30 g. of sodium borohydride and 135 g of iodine instead of methane sulfonic acid to provide the title compound.

Yield : 26 gms (% Yield: 93.5%) ; Purity by HPLC: 98.6%.

Example -19: Preparation of (+)-3-N,N-dimethylamino-3-phenyl propanol using L(+) tartaric acid

42.5gr. of L-(+)-tartaric acid, 722.5ml. of acetone and 255ml. of ethanol were charged in a clean and dry 2 lit. 4 neck RBFlask and stirred for aboutl Omin. 50gr. of 3-N,N-dimethyl- 3-phenyl propanol was added at about 30°C and heated to dissolve at 55-58°C,the clear solution was observed. Then the solution was maintained at 55-58°C for 30-45min. and filtered under hot condition to provide (+)-3-N,N-dimethylamino-3-phenyl propanol -L-tartaric acid salt.

Dry wt: 28.5gr.; SOR = (+) 21.5° (1% CH 3 OH).

First Recrystallization

28.5gr. of above compound, 142.5ml. of ethanol and 1 1ml. of distilled water were charged in a clean and dry 500 ml. 4 neck RBFlask and heated to dissolve at 55-60°C. The resultant solution was maintained at 55-60°C for 30min. and then cooled to about 30°C. 150ml. of acetone was added and stirred for about lOmin. and filtered off the solid.

Dry wt: 17.5gr.; SOR = (+) 27.652° (1% CH 3 OH).

Second Recrystallization : Taken 17.5gr. of the recrystallized compound,87.5ml. of ethanol and 5ml. of distilled water at ambient temperature and heated to dissolve and stirred for 30min. at the same temperature. Then the reaction mass was cooled to ambient temperature. Added 100ml. of acetone at ambient temperature stirred for 30min. and filtered.

Dry wt: 12.5gr.; SOR = (+) 28.300° ( 1% CH 3 OH). Step b: Taken 12gr. the compound obtained above, 96ml. of distilled water at room temperature and stirred for 5min.Then added 3.5ml. of caustic lye at room temperature and stirred for lOmin.Then the reaction mass was extracted with (40ml.x3 times) of

dichloromethane. The dichloromethane layer was washed with (60ml.x2 times) of distilled water. Finally the dichloromethane was distilled under vacuum to provide the residue.

Residue wt: 5gr. : SOR = (+) 43.66 0 (0.6% CHC1 3 ); Purity by HPLC : 99.01%.

Example -20: Preparation of (+)-3-N,N-dimethylamino-3-phenyI propanol

Step-a: lOOgr. of racemic 3-N,N-dimethylamino-3 -phenyl propanol, 102.5gr. of (+)- Dibenzoyl-D-tartaric acid (DBTA), 80gr. of citric acid, 200ml. of ethyl alcohol and 1000ml. of water in a clean and dry 2 lit. 4 neck RBFlask. The resultant reaction mixture was heated to dissolve the contents. Dissolution was observed at 85-95°C.Then the reaction mass was stirred for 10-15min. at the same temperature. Then the solution was cooled to about 30 °C and stirred for about lhr. at the same temperature. The separated solid was filtered to obtain of (+)-3-N,N- dimethylamino-3-phenyl propanol dibenzoyl tartaric acid salt. Wet wt: 171 gr.

Recrystallisation of of (+)-3-N,N-dimethylamino-3-phenyI propanol dibenzoyl tartaric acid salt. :

171.0gr. of of (+)-3-N,N-dimethylamino-3-phenyl propanol dibenzoyl tartaric acid salt, 250ml. of ethyl alcohol and 1250ml. of water were charged into a clean and dry 2 lit. 4 neck RB Flask and heated to dissolve the contents. The dissolution was observed at 85-95°C and stirred for 10-15min. The reaction. solution was cooled to about 30 °C and the solid separated was filtered to obtain the pure compound. Dry wt: 100-103gr.; SOR: + 92.42° (1% MeOH).

Step-b: Taken lOOgr. of pure of (+)-3-N,N-dimethylamino-3-phenyl propanol dibenzoyl tartarate salt,200ml. of dichloromethane,800ml. of water at ambient temperature.Added caustic lye at room temperature till the P H =9-10 was observed.Then the reaction mass was stirred for 30min. at the room temperature. The dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane (2xl00ml.).The dichloro methane layers were combined and washed with water (2x100ml) .Finally the dichloromethane layer was distilled under vacuum to provide the title compound.

Wt: 30-32gr. SOR: (+) 41.0-45.0° (0.6% in CHC1 3 ) ; Yield: 64%; Purity by HPLC: 99.2%. Example -21: Preparation of Dapoxetine (la)

Mixture of S(+)-3-N,N-dimethyl amino-3-phenyl propanol (50 g), 1 -fluoronaphthalene (50g), sodium hydroxide (50 g.) in dimethyl sulfoxide (DMSO)(250ml) were taken in a RB Flask and stirred. The reaction mixture was heated to about 100°C and stirred for about 4 hours. After completion of the reaction, reaction mixture was cooled to about 30°C. The reaction mixture was poured into 1200ml water and extracted with toluene. The combined organic layer was washed with water and added dilute hydrochloric acid solution to the organic layer. The pH of aqueous layer was adjusted to about 9 with ammonia solution.

The separated solid was filtered and washed with water and dried to afford the title compound. Dry wt: 55gr. (%Yield: 64.7%); M.P: 75.1-76.2°C; SOR: ' (+) 1 16.15° (C-1% in CH 3 OH); Purity by HPLC: 99.9%.

Example-22: Preparation of Dapoxetine (la)

Same procedure as described in Ex-21 , but using 192gr. of potassium carbonate instead of sodium hydroxide.

Dry wt: 25gr. (21.25% of isolated yield); M.P: 74.9°-76.4°C; SOR = (+)1 14.6° (C=l% in CH 3 OH)

Example-23: Preparation of Dapoxetine (la)

Same procedure as described in Ex-21, but using 500ml. of THF instead of DMSO and 65-68°C of reaction temperature.

Dry wt: 30gr. (35.29% of isolated yield); SOR = (+) 114.3° (C=l% in CH 3 OH)

Example-24: Preparation of Dapoxetine (la)

Same procedure as described in Ex-21, but using 500ml. of 2-methyl tetrahydro furan instead of DMSO and 78-80°C of reaction temperature.

Dry wt: 32gr. (37.64% of isolated yield) ; SOR = (+) 113.8° (C=l% in CH 3 OH)

Example-25: Preparation of Dapoxetine (la)

Same procedure as described in Ex-21, but using 500ml. of 4-methyl 2-butanone, 50gr. of 3-S(+)-N,N-dimethylamino-3-phenylpropanol,163.5gr. of potassium carbonate,25ml. of D.H 2 0 and 75gr. of 1-Fluoro naphthalene.

Dry wt: 29gr. (34.1% of isolated yield) ;SOR = (+) 1 14.2° (C=l% in CH 3 OH). Example-26: Preparation of Dapoxetine hydrochloride

Taken 50gr. of dapoxetine, 250ml. of ethyl acetate at ambient temperature and heated to 45-50°C.Added 5gr. of special carbon and stirred for lOmin. at 45-50°C and the reaction mass was filtered through carbon bed. The carbon bed was washed with 50ml. of hot ethylacetate.The ethyl acetate layer was cooled to ambient temperature. Then added 50ml. of 18% Isopropyl alcohol hydrochloric acid mixture drop-wise within 45-60min.Then the reaction mass was stirred for 30min. at ambient temperature and cooled to 0-5°C.The reaction mass was filtered and the cake was washed with 50ml. of chilled ethyl acetate and dried at 90-95°C for 4hrs. to furnish 49gr. of the title compound.

Wt: 49 g. (%Yield: 87.53%); Purity by HPLC: 99.98%; Chiral purity: 99.98% and R-isomer: 0.012% ; SOR: (+) 130.72° (C=l% in CH 3 OH) ; Assay: 100.51%; M.P: 180-182°C.

Taken 50gr. of dapoxetine, 300ml. of toluene at about 30°C. Then the reaction mass was stirred for lOmin. at ambient temperature and then filtered. To the organic layer added 50ml. of 18% Isopropyl alcohol hydrochloric acid mixture drop-wise at ambient temperature within 30-60min. and stirred for 30min. at the same temperature. The reaction mass was cooled to 0-5°C and stirred for 30min. at the same temperature.Then,the solid formed was filtered and washed with 50ml. of chilled toluene.

Dry wt: 47.5gr. (%Yield: 84.9%; SOR: (+)128.190°(C=1% in CH 3 OH); M.P: 182.3-184.4°C; Purity by HPLC: 99.958% ; Chiral Purity: 99.978% and R-isomer : 0.022%.

50gr. of Dapoxetine and 150ml. of isopropyl alcohol were charged in clean and dry

500ml neck RB Flask and heated to dissolve the contents at 75°C.Then 5gr. of special carbon was added and stirred for lOmin. at the same temperature. The resulted solution was filtered and washed with 20ml. of hot isopropylalcohol.The isopropyl alcohol layer was cooled to ambient temperature. Then added 35ml. of 18% Isopropyl alcohol hydrochloric acid mixture drop-wise at ambient temperature within 30min. and stirred for 30min. at the same temperature. Then the reaction mass was cooled to 0-5°C, stirred for 30min. at the same temperature and filtered. The solid was washed with 25ml. of chilled isopropyl alcohol to provide the title compound.

Dry wt: 47gr. (%Yield: 84.07%); SOR : (+) 130.72°(C=1% in CH 3 OH) ; M.P: 181.2-183.7°C; Purity by HPLC: 99.9%; Purity by chiral HPLC: 99.98%.