FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970) &
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR PREPARATION OF ARYLOXY
ARYL PROPANAMINES"
Emcure Pharmaceuticals Limited,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to a novel and industrially applicable, cost-effective process for preparation of aryloxy arylpropanamines of general formula (I) having purity conforming to regulatory specifications. The invention specifically relates to the reaction of 3-aryl-3-propanolamines (II) with aryl fluorides (III) in presence of sodium sulphide as a base to provide aryloxy arylpropanamines (I) with minimal racemization.
BACKGROUND OF THE INVENTION
Various aryloxy arylpropanamines (I) such as fluoxetine, tomoxetine, duloxetine, dapoxetine belong to the class of potent and selective inhibitors of uptake of serotonin and norepinephrine. This class of compounds, which contain a stereocenter, can be resolved to obtain the enantiomerically pure forms such as R-(+)-fluoxetine, R-(-)-tomoxetine, S-(+)-duloxetine, S-(+)-dapoxetine; which have been found to be potent enantiomers having the desired therapeutic activity and are utilized in pharmaceutical preparations.

Wherein, Ar1 is phenyl, 2-thienyl
A and B are either 0-Ar2 or N(R]R2) and are interchangeable, wherein
R1 and R2 are either hydrogen or methyl and are interchangeable
Ar2is 1-naphthyl, 4-trifluoromethylphenyl
A may be located below (a) or above (P) the plane of reference or is planar.
The prior art discloses several methods for synthesis of aryloxy arylpropanamines (I) wherein they have been synthesized from the corresponding arylpropanolamines.
US 5,362,886 discloses the reaction of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxy-propanamine with 1-fluoronaphthalene in presence of sodium hydride and using dimethyl sulfoxide as a solvent. Sodium hydride is not preferred on an industrial scale as it is a potential hazard due to its pyrophoric nature in presence of moisture, which thereby necessitates stringent anhydrous conditions. Further, the reaction also requires anhydrous

dimethyl sulfoxide which is tedious and cumbersome to prepare on a commercial scale. Further, in case of enantiomerically pure substrate, a strong base such as sodium hydride is likely to cause considerable racemization leading to associated impurities in the final product, which then requires additional purification steps.
WO 2007/06132 discloses the reaction of aryl aminopropanol derivatives with various aryl halides to give the desired aryloxy aryl amines utilizing copper, palladium and nickel containing catalysts, in presence of bases such as alkali metal carbonates, bicarbonates or magnesium oxide.
WO 2009/19719 describes the preparation of 3-aryloxy-3-propanolamines starting from hydroxyl protected aryl propanolamines. The synthetic sequence comprises protection of the hydroxyl group of thienyl propanolamine with a suitable acid chloride or anhydride, followed by condensation of the 3-O-protected intermediate with 1-fluoronaphthalene in presence of a base and a phase transfer catalyst.
Although this process avoids strong bases, however, requirement of a phase transfer catalyst coupled with an additional step of hydroxyl protection increases the number of unit operations, leading to decreased reactor occupancy and increased costs.
WO 2008/35358 describes synthesis of l-phenyl-3-naphthaloxy-N,N-dimethylpropan-l-amine wherein l-phenyl-3-chloropropan-l-ol is reacted with 1-naphthol in presence of potassium carbonate and dimethyl sulfoxide to give l-phenyl-3-naphthyloxypropan-l-ol , followed by reaction of the alcohol with methane sulfonyl chloride and subsequent reaction of the sulfonyloxy derivative with dimethylamine gas.
US 6,677,485 discloses synthesis of N-methyl-3-[4-trifluoromethylphenoxy]-3-phenyl-propylamine by reaction of N-methyl-3-hydroxy-3-phenylpropylamine with l-chloro-4-trifluoromethylbenzene using potassium hydroxide as a base and polyethylene glycol or crown ethers as catalysts.
US 7,645,890 discloses use of phase transfer catalysts such as tetrabutyl ammonium bromide or crown ethers along with a base like potassium hydroxide for the condensation

reaction between l-(N,N-dimethyl-3-hydroxypropylamino)thiophene derivative and 1-naphthyl halide. Use of expensive phase transfer catalyst such as crown ethers considerably increases the cost which renders the process industrially unviable.
Thus, it would be evident that in all prior art methods, factors such as utilization of strong bases, heavy metal catalysts, expensive reagents or inclusion of derivatization steps in the reaction sequences hamper the viability of the prior art methods on commercial scales.
Thus, there still exists a need for a convenient, industrially applicable process for preparation of aryloxy arylpropanamines which results in products having impurity levels complying with the regulatory norms. The method disclosed in the present invention avoids use of strong bases like alkali hydride or alkoxide bases which are difficult to handle due to their moisture sensitive nature or phase transfer catalysts or highly specific catalytic reagents and also eliminates the need for protection or derivatization of the hydroxyl group of propanolamines to obtain the desired aryloxy arylpropanamines.
The present inventors have tried out several synthetic procedures in search of a suitable base for the reaction between aryl propanolamine of formula (II) and the halogenated aryl derivative of formula (III). The choice of the base depended on ease of operation on industrial scale, circumventing the use of costly catalysts and also for avoiding racemization of either the reactant or the product during the course of the reaction or in the process of isolation of the pharmaceutically active aryloxy arylpropanamines,

Wherein, Ar1 is phenyl, 2-thienyl
A and B are either 0-Ar2 or N(R1R2) and are interchangeable, wherein
R1 and R2 are either hydrogen or methyl and are interchangeable
Ar2is 1-naphthyl, 4-trifluoromethylphenyl
A may be located below (a) or above (P) the plane of reference or is planar.

It was an unexpected finding by the inventors that all these objectives could be achieved by utilizing sodium sulfide as a base. Significantly, the condensation reaction between compounds of formula (II) and (III) was facile and proceeded with minimal degree of racemization, which was a distinct advantage especially in case of enantiopure reactants and products.
OBJECT OF THE INVENTION
An objective of the present invention is to provide a synthetic method for preparation of aryloxy arylpropanamines (I) which avoids the bases used in prior art which led to partial racemization of the product.
Another object of the invention is to utilize a base which leads to minimal racemization of the product.
Yet another object of the invention is to avoid utilization of catalysts or costly reagents for preparing aryloxy arylpropanamines (I).
Yet another object of the invention is to provide a convenient and industrially applicable process for preparation of aryloxy arylpropanamines (I) in high yields and with good purity by utilizing sodium sulfide as a base for reaction of arylpropanolamines of formula (II) with aryl fluorides (III).
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of aryloxyaryl propanamines (I) by reaction of aryl propanolamines (II) with aryl fluorides (III) in presence of a base like sodium sulfide under mild reaction conditions wherein any racemization especially in the case of enantiopure products is minimized below regulatory limits.

An aspect of the invention relates to a process for the preparation of aryloxyaryl propanamines (I) comprising reaction of aryl propanolamines of formula (II) with aryl fluorides of formula (III) in presence of sodium sulfide and dimethyl sulfoxide as a solvent at a temperature of 65-85°C and isolating aryloxy arylpropanamines of formula (I) having desired purity.
These objectives of the present invention will become more apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
During the experimentation aimed at obtaining aryloxy arylpropanamines of formula (I), having desired purity, the present inventors observed that anhydrous conditions, especially use of anhydrous solvent and moisture sensitive bases posed serious problems on commercial scale. The strong bases utilized in prior art were highly moisture sensitive bases like sodium hydride or when alkali metal hydroxides or alkoxides were employed, they had to be used in combination with a phase transfer catalyst. Further, when enantiomerically pure aryl propanolamines (II) were used, many of these bases caused high degree of racemization which hampered the purity of the resulting aryloxy aryl propanamines and incurred additional purification steps for removal of the undesired isomer.
Extensive experimentation was carried out by the present inventors for the selection of appropriate base for reaction of aryl propanolamines (II) with aryl fluorides of formula (III), and it was unexpectedly found that when sodium sulfide was employed as a base the reaction was facile and the degree of racemization was minimized to a large extent. Further, sodium sulfide could be handled very easily on commercial scale and the reaction produced the desired compound in high yield and desired purity and without any additional step of purification.

Scheme 1: Method embodied in the present invention for the preparation of aryloxy arylpropaiiamines (I)
Duloxetine (Ia) is a representative example of aryloxy arylpropanamines (I) and it was found that the product could be isolated without any additional step of purification. Similarly, the same method was employed to obtain other aryloxy arylpropanamines (I).

Scheme 2: Method embodied in the present invention for the preparation of Duloxetine (la)
The inventors also found that the method was widely applicable and could be applied to the synthesis of other aryloxy arylpropanamines derivatives as disclosed in Table-1.

Wherein, Ar1 is phenyl, 2-thienyl
A and B are either 0-Ar2 or N(R1R2) and are interchangeable, wherein
R1 and R2 are either hydrogen or methyl and are interchangeable
Ar2 is 1-naphthyl, 4-trifluoromethylphenyl
A may be located below (a) or above (p) the plane of reference or is planar.


Table 1: Aryloxy arylpropanamines (I)
In a specific embodiment, the reaction of (S)-N-methyl-3-hydroxy-3-(2-thienyl) propanamine (IIa) with 1-fluoronaphthalene of formula (IIIa) was carried out in presence of sodium sulfide as a base and dimethyl sulfoxide as solvent. The reaction was carried out in the temperature range of 65 - 85 C.
The reaction was found to be facile with minimal formation of the undesired isomer. After completion of the reaction, as monitored by HPLC, the reaction mixture was cooled and extracted with toluene. Separation and concentration of the organic layer yielded Duloxetine free base of formula (la).
It was found that the developed method could be applied to all the aryloxy arylpropanamines molecules disclosed in table I.
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

EXAMPLES
Example 1: Synthesis of (+)-(5)-N-Methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl) --propan-1-amine [Duloxetine (la)]
(S)-N-Methyl-3-hydroxy-3-(2-thienyl) propanamine (100.0 g) was suspended in dimethyl sulfoxide (1000 ml) at room temperature with stirring. Sodium sulfide (55-60%, 150 g) was added to the mixture followed by the gradual addition of 1-fluoronaphthalene (100.2 g). The reaction mixture was heated between 65 and 85°C. After completion of the reaction, based on HPLC, the reaction mass was cooled and extracted with toluene (1000ml). Concentration of the organic layer yielded Duloxetine free base (la). Yield: 150.3 gms (88%) Purity: 98.61%
Example 2: Synthesis of N-methyl-3-phenyl-3-[4-(trifluoromethyI) phenoxy]--propan-1-amine [Fluoxetine, (lb)]
l-Phenyl-3-(methylamino)propan-l-ol (10.0 g) was suspended in dimethyl sulfoxide (100 ml) at room temperature with stirring. Sodium sulfide (55-60%, 15.7 gm) was added to the mixture followed by the gradual addition of 4-fluoro-trifluoromethylbenzene (11.8 g). The reaction mixture was heated between 75 and 80°C, till completion of the reaction, based on HPLC. The reaction mixture was cooled and quenched with water. The reaction mixture was extracted with toluene; the organic layer was separated and concentrated to give Fluoxetine free base. Yield: 12.4 g Purity: 99.1%
Example 3: Synthesis of (5)-(+)-N,N-dimethyl-3-(naphthalen-l-yloxy)-l-phenylpropan-l-amine [Dapoxetine (Id)]
(S)-N,N-Dimethyl-l-phenyl-propane-3-ol-l-amine (10.4 g) was suspended in dimethyl sulfoxide (150 ml) at room temperature with stirring. Sodium sulfide (24.2 g, 50-60 %) was added to the mixture followed by the gradual addition of 1- fluoronapthalene (9.78 g). The reaction mass was heated between 75 to 80°C, till completion of the reaction, as monitored by HPLC. After completion of the reaction, the reaction mixture was cooled

and quenched with water. The reaction mixture was extracted with toluene; the organic layer was separated and concentrated to give Dapoxetine free base (Id). Yield: 13.1 g Purity: 99.3%

We claim,
1) An improved process for the preparation of aryloxy arylpropanamines of formula (I) comprising reaction of aryl propanolamines of formula (II) with aryl fluorides of formula (III) in presence of sodium sulfide as base and dimethyl sulfoxide as a solvent at a temperature of 65-85°C and isolating aryloxy arylpropanamines of formula (I) having desired purity.
2) A process as claimed in claim 1, wherein the aryloxy arylpropanamine of formula (I) was isolated by cooling and quenching of the reaction mixture with water, adding an organic solvent and concentrating the organic layer to get the compound of formula (I) having the desired purity.
3) A process as claimed in claim 1, wherein the aryloxy arylpropanamines are selected from the group comprising of Duloxetine, Fluoxetine, Norfluoxetine and Dapoxetine.
4) A process as claimed in claim 2, wherein the solvent is toluene.