Description:FIELD OF INVENTION
The present invention relates to an improved one-pot and eco-friendly process for the preparation of racemic Dapoxetine (or) its salt thereof.

BACKGROUND OF THE INVENTION
Dapoxetine hydrochloride (INN, brand name Priligy) is a short-acting selective serotonin reuptake inhibitor (SSRI) and is marketed for the treatment of premature ejaculation (PE) in men. Dapoxetine is a first agent to be developed specifically to treat premature ejaculation. The drug Dapoxetine hydrochloride was first available on 2009 in Europe; it is used for the oral, on-demand treatment of PE in men between 18 to 64 years of age.

Dapoxetine hydrochloride is chemically known as N,N-Dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine Hydrochloride. The structure of Dapoxetine hydrochloride is represented by the formula (I).

Formula-I

Dapoxetine is first disclosed in a patent EP0288188. The patent provides process for the preparation of various 1-phenyl-3-naphthalenyloxypropanamies along with their pharmaceutically acceptable salts, including resolution to get optically active enantiomer.
The patent US5135947 also discloses various 1-phenyl-3-naphthalenyloxypropanamies and their analogues with their pharmaceutically acceptable salts and their use in selective serotonin receptive inhibitors. The process as per the patent US’947 for the preparation of Dapoxetine hydrochloride is depicted here in scheme-1,

Scheme-1

The reported process for the preparation of compound of formula (l) uses sodium hydride which is hazardous and difficult to handle on industrial scale.

The patent US 5292962 discloses a process for the preparation of Dapoxetine and its salts. The process as per the patent US’962 for the preparation of Dapoxetine hydrochloride is depicted here in scheme-2,

Scheme-2
In the patent US’962 discloses novel intermediates to 1-phenyl-3-naphthalenyloxyproanamines i.e. through 1, 3-dihydroxy compound.

In a PCT Publication WO2008/035358 describe a process for the preparation of Dapoxetine hydrochloride compound of structural formula-1, wherein racemic (±) N, N-dimethyl-2-[2-(naphthalenyloxy) ethyl] benzene methanamine is being resolved by chiral acid such as (+)-di-p-toluyl tartaric acid.

And the process of WO’358 involves a multistep preparation of Dapoxetine starting from Benzene and chloropropionyl chloride under Friedel-Crafts reaction. The preparation of Dapoxetine hydrochloride is depicted here in scheme-3,

Oliver Torre et al; in a Tetrahedron Asymmetry 17 (2006), P 860-866, describe the Lipase-catalyzed resolution method for the preparing of (S)-Dapoxetine.

Pinak M. Chincholkar et al; in a Tetrahedron 65 (2009) 2605–2609, describe the synthesis of (S)-Dapoxetine from enantiopure 3-hydroxy azetidin-2-one.

Shafi A. Siddiqui et al; in a Tetrahedron: Asymmetry 18 (2007) 2099–2103, describe the synthesis of (S)-Dapoxetine from Sharpless asymmetric dihydroxylation, Barton–McCombie deoxygention, and Mitsunobu reaction as the key steps.

Soyeong Kang et al; in JOC, 2010, 75, 237-240, describes a method for the preparation of enantioselective synthesis of Dapoxetine from 3-phenyl-1-propanol.
Apart from the above most of the publications are reported the process for the preparation of enantioselective synthesis of Dapoxetine (or) Dapoxetine hydrochloride. Some of the reported prior art publications are CN113880721, CN113801027, CN113461553, CN112159328, CN110845369, CN109503397, CN107935868, CN107473977, CN107382751, CN106883133, CN106748817, CN106397227, CN106242980, CN105732309, CN104628584, CN104610076, CN103396320, CN103373931, CN103304434, CN102942496, CN102911065, CN102746170, CN102229538, CN101367739 , CN103664659 , CN103664660, CN111763700, CN100402488, EP2749553, IN359321, IN311824, IN305557, IN287150 , IN300076, IN2011MU00539, IN2011CH00898, IN2011CH02486, WO2011058572, WO2014024205.

One and most of the above mentioned literatures are discloses the use or preparation of (S)- Dapoxetine hydrochloride as a final product. Thus still there is a need to develop a process for the preparation of racemic Dapoxetine hydrochloride by avoiding the drawbacks associated with the prior art process.

OBJECT OF THE INVENTION:
The main objective of the present invention is to provide a economical and commercial feasible process for the preparation of racemic Dapoxetine (or) Dapoxetine hydrochloride compound of formula-I

In an objective of the present invention is to provide an improved one-pot process for the preparation of Dapoxetine hydrochloride compound of formula-I

Formula-I

SUMMARY OF THE INVENTION
The present invention is to provide a process for preparation of racemic Dapoxetine hydrochloride a compound of formula I, comprises steps of,

Formula-II
(i) reduction of compound of formula-II, with suitable reducing agent to give compound of formula-III.

Formula-III
(ii) treating the compound of formula-III with a-Naphthol in presence of suitable base and solvent to give compound of formula-IV

Formula-IV

(iii) activating the hydroxyl group with suitable activating agent and base to give compound of formula-V

Formula-V
(iv) treating the compound of formula-V with dimethylamine optionally in presence of catalyst to give Dapoxetine free base
(v) conversion of step-(iv) to suitable acid addition salt of Dapoxetine as a final product.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1 is a characteristic XRPD of racemic Dapoxetine hydrochloride
Figure-2 is a characteristic DSC of racemic Dapoxetine hydrochloride
Figure-3 is a characteristic NMR spectra of racemic Dapoxetine hydrochloride
Figure-4 is a characteristic IR spectrum of racemic Dapoxetine hydrochloride

DETAILED DESCRIPTION OF THE INVENTION
The first aspect of the invention is to provide a process for preparation of racemic Dapoxetine hydrochloride a compound of formula I, comprises steps of,

Formula-II
(a) reduction of compound of formula-II, with suitable reducing agent and solvent at a to give compound of formula-III.

Formula-III
(b) treating the compound of formula-III with a-Naphthol in presence of suitable base, solvent and optionally in presence of catalyst to give compound of formula-IV

Formula-IV
(c) activating the hydroxyl group with suitable activating agent and base to give compound of formula-V

Formula-V
(d) treating the compound of formula-V with dimethylamine optionally in presence of catalyst to give Dapoxetine free base
(e) conversion of step-(iv) to suitable acid addition salt of Dapoxetine as a final product.

The second aspect of the invention is to provide a one-pot process for the preparation of racemic Dapoxetine hydrochloride of formula-I
The third aspect of the invention is to provide a high pure racemic Dapoxetine hydrochloride of formula-I

The forth aspect of the invention is one or more step involves the use of catalyst, to increase rate of the reaction.

The fifth aspect of the invention is used to preparation of (S)- Dapoxetine hydrochloride by using racemic Dapoxetine.

The process of the present invention can be represented schematically as follows

Scheme-2
The solvent is selected from water, hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents (or) its mixture thereof.

Suitable solvent in step-(a) is selected from water, hydrocarbon solvents, ether solvents and alcohol solvents (or) its mixture thereof; more preferably alcohol (or) hydrocarbon solvents.

Suitable solvent in step-(b), (c), (d) is selected from polar aprotic solvents, hydrocarbon solvents, chlorinated solvents (or) its mixture thereof.

Suitable solvent in step-(e) is selected from alcohol solvent.

The ‘‘base’’ used in the present invention can be selected from but not limited to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; ammonia; organic bases’’ like "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; dimethylamine, diethylamine, diisopropyl mine, diisopropylethylamine (DIPEA), diisobutylamine, trimethylamine, triethylamine, triisopropylamine, tributylamine, tert.butyl amine, pyridine, piperidine, 4-dimethylamino pyridine (DMAP), quinoline, imidazole, N-methylimidazole, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), dimethylaniline, N-methylmorpholine (NMM), l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like;

The catalyst used in the reaction is selected from but not limited to phase transfer catalyst.

Hydroxyl group is converted to an ester of a strong acid. Selected from sulfonate esters such as mesylate and tosylate esters; more preferably mesylate

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Example-1: Preparation of 3-chloro-1-phenylpropan-1-ol
To a stirring solution of 3-Chloro-1-phenylpropan-1-one (100 g, 0.6 mol) in toluene (277 ml, 2.8 vol) was stirred for 10-15 min at 25-30 °C under nitrogen atmosphere. To this sodium borohydride (13.3 g) was added slowly at 0-5°C for 15-30 min. Followed by methanol (111 ml, 1.11 vol) was added slowly at a same temperature for 120-180 min. After completion of methanol addition the resultant reaction mass was stirred for 60 min at 0-5°C. The reaction mass temperature was further raised to 10-15°C and maintain for 120 min. The progress of the reaction was check with TLC, after completion of the reaction the reaction mass was cooled to 0-5 °C and adjust the pH to 5.0-5.5 with acetic acid (55 ml, 0.55 vol). The reaction mass was diluted with purified water (188 ml, 1.88 vol) below 20°C and the mass was stirred followed by settled for 30 min. The aqueous layer was extracted with toluene (2 x times). Then the combined organic layer was washed with 10% sodium bicarbonate solution, followed by water and sodium chloride solution. This organic layer was dried over sodium sulfate and used as such in next stage.
Example-2: Preparation of 3-(Naphthalen-1-yloxy)-1-phenylpropan-1-ol
To a stirred solution of a- Naphthal (73 g, 0.92 mol) in DMF (277 ml, 2.77 vol) was added for 10-15 min at 25-35°C. To this solution sodium hydroxide (18.9 g, 0.189 vol) was added below 400C. This mass was stirred for 50-60 min at 25-35°C. To this above obtained Example-1 organic layer was added and stirred at 75-80°C for 120 min. The progress of the reaction mass was checked by TLC. After completion of the reaction the reaction mass was cooled to 25-35°C and water was added stirred for 10-15 min and then settled for 20 min. Then the organic layer was separated and the aqueous layer was extrated twice with toluene. The combined organic layer was washed with 5% sodium hydroxide solution. And the resultant reaction mass was dried over sodium sulfate. The obtained organic layer was used further stage without isolation.

Example-3: Preparation of Dapoxetine Hydrochloride
To the above obtained Example-2, triethylamine (94.4 g, 0.93 mol) was added at 25-30°C for 30 min. Then the reaction mass was cooled to 0-5°C and methanesulfonyl chloride (78.8 g, 0.688 mol) in toluene (83.3 ml, 0.833 V) was added slowly over a period of 90-120 min. The resultant reaction mass was stirred for 120 min at 0-5 °C. The progress of the reaction was monitored by TLC. After completion of the reaction mass was used for next stage

To the above organic layer TBAB (2.0 g) was added at 0-5°C, and aq Dimethyl amine (500 g, 5.0 V) was added at same temperature. After completion of addition the reaction mass temperature raised to 25-30°C and stirred for 36 h. The progress of the reaction mass was checked with TLC, after completion of the reaction the reaction mass was diluted with water and stirred for 15 min. Organic layer was separated from the reaction mass and the aqueous layer was extracted with dichloromethane (2 x times). The combined organic layer was slowly added a mixture of water (277 ml, 2.77 V), Conc. Hydrochloric acid (138.8 ml, 1.388 V) and Dimethyl formamide (138.8 ml, 1.388 V) at 25-30°C and stir for 15 min. Separate the both the layer. The aqueous layer was extracted with dichloromethane (3 x times). The combined organic layer was adjusted to the pH 10.0-11.0 using 10% NaOH solution. Further the reaction mass was stirred for 15-30 min and both the layers was separated. The organic layer was washed with water (2 x times). And the combined organic layer was dried over sodium sulfate and filtered. The filtrate was distilled out under vacuum below 50°C. The above obtained residue was degassed to remove traces of dichloromethane.
To the obtained residue methanol (222 ml, 2.22 V) was added and stirred for 10-15 min at 50 °C. Adjust the reaction mass pH to 1.0-2.0 with IPA. HCl (70ml, 0.7V) at 20-30°C then the reaction mass temperature raised to 45-50 °C. To this activated carbon (0.55 g, 0.055 V) was added and reaction mass was stirred for 60 min. Filter the reaction mass through hyflo bed and wash with methanol (55 ml, 0.55 V). The obtained filtrate was distilled out under vacuum below at 50°C. After distillation IPA (50ml, 0.5V) was added and co-distilled with methanol to remove the methanol traces. To the residue IPA (500ml, 5.0V) was added and heated to 50-55°C for 60 min. The reaction mass was slowly cooled down to 0-5 °C and filter. The obtained solid was washed with chilled IPA (50 ml, 0.5V) and dried under vacuum at 60-65°C for 7-8 h to get desired Dapoxetine hydrochloride of formula-1 (Yield 110 g)
, Claims:We claim:
1. A process for the preparation of Dapoxetine hydrochloride, of formula-1,

Formula-I
comprises steps of,
(a) reduction of compound of formula-II,

Formula-II
with suitable reducing agent and solvent to give compound of formula-III.

Formula-III
(b) treating the compound of formula-III with a-Naphthol in presence of suitable base, solvent and optionally in presence of catalyst to give compound of formula-IV

Formula-IV
(c) activating the hydroxyl group with suitable activating agent and base to give compound of formula-V

Formula-V
(d) treating the compound of formula-V with dimethylamine optionally in presence of catalyst to give Dapoxetine free base
(e) conversion of step-(d) to suitable acid addition salt of Dapoxetine as a final product.

2. The process according to the claim-1, suitable solvent of the invention is selected from water, hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents

3. The process according to the claim-2, the more suitable solvent in step-(a) is selected from water, hydrocarbon solvents, ether solvents and alcohol solvents (or) its mixture thereof; more preferably alcohol (or) hydrocarbon solvents. Suitable solvent in step-(b), (c), (d) is selected from polar aprotic solvents, hydrocarbon solvents, chlorinated solvents (or) its mixture thereof. Suitable solvent in step-(e) is selected from alcohol solvent.

4. The process for preparation of racemic Dapoxetine hydrochloride, of formula-1, comprises steps of,
(a) reduction of compound of formula-II,

Formula-II
with sodium borohydride, in presence of alcohol and hydrocarbon solvent to give compound of formula-III.

Formula-III
(b) the compound of formula-III is treated with a-Naphthol in presence of inorganic base, hydrocarbon and polar aprotic solvent to give compound of formula-IV

Formula-IV
(c) treating the compound of formula-IV is with methanesulfonyl chloride and organic base and hydrocarbon solvents to give compound of formula-V

Formula-V
(d) without isolating the compound of formula-V is treated with dimethylamine optionally in presence of catalyst to give Dapoxetine free base.
(e) optionally isolating the compound of formula-V is converted to its hydrochloride salt thereof.

5. The process according to the claim-1, Dapoxetine (or) its hydrochloride salt is prepared in one-pot process.

6. The process according to the claim-4, the most suitable solvent in one or more stage is hydrocarbon solvent, alcohol (or) mixture thereof.

7. The process according to the claim-4, step-(d) dimethylamine is used as an aqueous dimethylamine (or) dimethylamine gas; more preferably aqueous dimethylamine.

8. The process according to the claim-4, step-(d) catalyst is phase transfer catalyst, more preferably TBAB, TBAC.

9. The process according to the claim-4, step-(e) saltification is performed using HCl in alcohol (or) EtOAc; more preferably IPA in HCl.

10. The process according to claim-1, is further comprised to the preparation of (S)-Dapoxetine hydrochloride.