TECHNICAL FIELD
The present disclosure is related to a process for preparation of duloxetine hydrochloride, an Active Pharmaceutical Ingredient [API].
BACKGROUND
The present disclosure relates to an improved process for the preparation of Duloxetine Hydrochloride, (S)-(+)-N-methyl-3(l-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride, compound of formula (VI).
Duloxetine hydrochloride is currently marketed as an anti-depressant and inhibits the uptake of both norepinephrine and serotonin. Duloxetine is disclosed in U.S. Pat. Nos. 5,023,269 and 4,956,388 by Robertson, et al. The synthesis of duloxetine is discussed in more detail by Berglund, R. A., Org. Proc. Res. Devel, 1, 328 (1997) and Deeter, et al., in Tetrahedron Letters, 31(40), 7101-04 (1990) and aspects patented in U.S. Pat. Nos. 5,362,866 and 5,491,243.
U.S. Pat. No. 5,362,866 discloses a process to synthesize duloxetine via arylation of a
dimethylamino alcohol, with 1-fluoronaphthalene which may be recovered as the
phosphoric acid salt if desired. The dealkylation yields duloxetine as a final product.
The present invention is advantageous in reducing the racemization caused due to
elevated temperature formation and hydrolysis in polyethylene glycol.
OBJECTIVES
The first objective of the disclosure is to provide an improved process for the
preparation of duloxetine hydrochloride.
Second objective of the disclosure is to prevent racemization of duloxetine
hydrochloride followed by preventing the formation of its unwanted isomer.
STATEMENT OF DISCLOSURE
Accordingly, the present disclosure is in relation to a process for
preparation of (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-
yl)propan-l-amine hydrochloride, comprising steps of: preparing (S)-(+)-
N,N-dimethyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine by reacting
(S)-(-)-3-(dimethylamino)-l-(thiophen-2-yl)propan-l-ol and 1-Flouoro Naphthalene in
the presence of Potassium benzoate and NaH at room temperature in an organic

solvent; reacting (S)-(+)-N,N-dimethyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine with ethychloroformate in the presence of a base and organic solvent to get (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate; hydrolyzing (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate in Poly Ethylene Glycol-400 or polyethylene glycol-200 with Potassium hydroxide, sodium hydroxide; dissolving hydrolyzed compound from step c in ethyl acetate and reacting with oxalic acid (dissolved in acetone) to get (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine oxalate; (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine prepared by treating (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine oxalate with aqueous ammonia in water and extracted into ethyl acetate; and (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine dissolved in a mixture of ethyl acetate and acetone and treated with HC1 to get (S)-(+)-N-methyl-3-(naphthalen-1 -yloxy)-3-(thiophen-2-yl)propan-1 -amine hydrochloride.
DETAILED DESCRIPTION
This invention is to provide an improved process for the synthesis of Duloxetine hydrochloride, (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan -1-amine hydrochloride in good yield, in large amounts and with desired purity.
This invention includes a process for preparing (S)-(+)-N,N-dimethyl-3-(naphthalen-l-
yloxy)-3-(thiophen-2-yl)propan-l-amine comprising reacting (S)-(-)-3-
(dimethylamino)-l-(thiophen-2-yl)propan-l-ol with sodium hydride and 1-fluoronaphthalene in dimethylsulfoxide at ambient temperature. This process reduces the racemization caused due to elevated temperature.
Another embodiment of this invention includes a process for preparing (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate comprising reacting (S)-(+)-N,N-dimethyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine with ethyl chloroformate in toluene in presence of diisopropyl ethyl amine at reflux temperature.
A further embodiment of the present invention includes a process for preparing (S)-(+)-
N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine comprising

hydrolysis of (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate using potassium hydroxide in polyethylene glycol-400 at 65-70° C.
Additionally, the present invention provides a process for preparing (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine hydrochloride from (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine by converting it into its oxalate salt or by direct conversion to Duloxetine hydrochloride.

Schematic representation: Preparation of (S)-(-t-)-N-methvl-3(l-naphthalenvloxv)-3-(2-thienvl)propanamine hydrochloride, compound of formula (VI)
This invention includes a process for preparing (S)-(+)-N, N-dimethyl-3-(naphthalen-l-
yloxy)-3-(thiophen-2-yl)propan-l-amine comprising reacting (S)-(-)-3-
(dimethylamino)-1 -(thiophen-2-yl)propan-1 -ol with 1 -fluoronaphthalene.
To date most processes utilized to synthesize duloxetine proceed via an arylation step involving sodium hydride and Dimethyl sulfoxide at elevated temperatures. The reaction at elevated temperatures induces partial racemziation resulting in the formation

of unwanted isomer of Duloxetine hydrochloride. Therefore, in the improved process, the reaction is carried out at ambient temperature to reduce the formation of unwanted isomer.
Also, the tedious workup procedure to remove unreacted 1-Fluoronaphthalene is avoided and the product is extracted directly to Ethyl acetate. The disclosed workup procedure includes adjusting the pH of the reaction mixture to acidic by using Acetic acid. 1-Fluoronaphthalene was extracted to n-hexane. The product was then extracted from its acetate salt by adjusting the pH to basic using liq. ammonia solution. Now in the improved process, acid base work up is avoided and the product is directly extracted to ethyl acetate. Unreacted 1-Fluoronaphthalene is subsequently removed by oxalate salt formation or hydrochloride formation.
Another embodiment of this invention includes a process for the preparation of (S)-(+)-
ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate comprising
reacting (S)-(+)-N,N-dimethyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-
amine with ethyl chloroformate in toluene in presence of diisopropyl ethyl amine at reflux temperature. With this combination of reagents i.e., Ethyl chloroformate, diisopropyl ethylamine and toluene, the reaction time is about 15 minutes to lhour. Advantageously, this process provides a better pathway to obtain (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate in its pure form in good yields.
A further embodiment of the present invention includes a process for preparing (S)-(+)-
N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine comprising
hydrolysis of (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate using potassium hydroxide in polyethylene glycol-400 at 30° C to 100° C. This process is very effective in hydrolyzing (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate to secondary amine. The process followed is novel, introduces the use of Polyethylene glycol-400 as a solvent in hydrolysis of (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate.
Additionally, the present invention provides a process for preparing (S)-(+)-N-methyl-3-(l-naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine hydrochloride from (S)-

(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine by converting into its oxalate salt. This process provides a pathway to remove unreacted 1-Fluoronaphthalene which was carried over from O-arylation stage and improves the purity of Duloxetine free amine in good yields.
Also, (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl) propan-1-amine is directly converted into Duloxetine hydrochloride avoiding oxalate salt formation. This process reduces the process time by one step providing required quality of Duloxetine hydrochloride. Efforts were made to circumvent the purification step as it involves the loss of yield to as much as 45% in oxalate salt formation. In this process, the amine is directly converted to its Hydrochloride salt by treating it with Cone. Hydrochloric acid in a mixture of Ethyl acetate and Acetone.
In another embodiment, the duloxetine amine was purified by converting into its oxalate salt in a mixture of ethyl acetate and acetone. This process provides a new method for purification of Duloxetine amine which also removes unreacted 1-Fluoronaphthalene which was carried over from O-arylation stage. The oxalate salt thus obtained is further converted into Duloxetine hydrochloride in its pure form.
In another embodiment, Duloxetine free amine is converted into Duloxetine hydrochloride in the mixture of Ethyl acetate and Acetone in presence of Cone. Hydrochloric acid. This improved process provides a method for hydrochloride formation in its purest form. This improved process avoids purification of Duloxetine hydrochloride.
Advantages of the process:
1) In stepl, the reaction was carried out at 25 to 30° C to avoid partial racemization as against other processes which were carried out at 65-70° C. This is advantageous as the reagent used here is sodium hydride.
2) The workup procedure in step 1 to remove unreacted 1-Fluoronaphthalene is avoided as it can be removed in subsequent steps by oxalate formation or hydrochloride formation.

3) Effective hydrolysis of (S)-(+)-ethyl methyl (3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate to secondary free amine is carried out in PEG-400 using KOH pellets. The process followed is novel as it introduces the use of Polyethylene glycol-400 as a solvent in hydrolysis of (S)-(+)-ethyl methyl (3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl) carbamate. The technology of the instant Application is further elaborated with the help of following examples. However, the examples should not be construed to limit the scope of the invention. Example: 1
Preparation of (^)-(+)-NJN-dimethvl-3-(naphthalen-l-vloxv)-3-(thiophen-2-vDpropan-l-amine
lOg of (S)-(-)-3-(dimethylamino)-l-(thiophen-2-yl)propan-l-ol was dissolved in 60 mL of dimethyl sulfoxide at 25° C. To the soln. 2.3g of NaH (1.1 eq neat) was added slowly as 60% dispersion in mineral oil with vigorous stirring. Reaction mass was stirred for 15 minutes. 0.86g of Potassium benzoate was added and stirred at the 25 to 30° C for 15 minutes. 9.46g of 1-Flouoro Naphthalene was added slowly to the reaction mixture. After complete addition, mixture was stirred at 25 to 30° C for 48h. Reaction mixture was quenched by pouring it into crushed ice. 60mL of Ethyl acetate was added and stirred for 10 minutes. The biphasic mixture was filtered through celite. Separated the layers & aqueous phase was stirred again with 30mL Ethyl acetate. Separated the layers & aqueous phase was extracted with 30mL Ethyl acetate. Combined extract was washed with water. Organic layer was dried over sodium sulfate & concentrated under vacuum at 40-45° C to obtain syrup.
Example: 2
Preparation of (^)-(+)-N-methvl-3-(naphthalen-l-vloxv)-3-(thiophen-2-vl)propan-
1-amine
8.3 g of (S)-(+)-N,N-dimethyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine syrup was dissolved in 83mL of Toluene, 6mL of N, N-Diisopropyl ethyl amine was added and the mixture was stirred for 10 minutes. 7.7mL of Ethyl chloroformate was added drop wise. Temperature was raised to reflux and reaction mass was refluxed for 10 minutes. 0.46mL N, N-Diisopropyl ethyl amine and 0.25mL Ethyl chloroformate was added simultaneously to the reaction mass. Soln was stirred for 15 minutes.

0.46mL of N,N-Diisopropyl ethyl amine and 0.25mL of Ethyl chloroformate was added again to the reaction mass. Mixture was stirred for 30 minutes. Temperature of the reaction mass was brought to 25° C. Reaction mass was quenched with 17mL of water & separated the layers. Organic layer was washed twice with 8mL of 1.5N HC1, washed with 8mL of 10% NaHC03 followed by 8mL of water & 4mL of saturated sodium chloride soln. Organic layer was dried over sodium sulfate and was concentrated to syrup.
lOg of (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate
syrup was dissolved in 50mL of Poly Ethylene Glycol-400. 12.lg of Potassium
hydroxide pellets were added to the reaction mass. Reaction mass was maintained at
65-70° C for 16h. Reaction mass was brought to 25° C and lOOmL of water was added
to the reaction mass. 50mL of Ethyl acetate was also added to the reaction mass and the
two phase mixture was filtered through celite. Separated the layers, aqueous layer was
extracted twice with Ethyl acetate. Ethyl acetate extracts were combined and the
combined extract was washed thrice with 50mL of water. Organic layer was washed
with lOmL of Saturated sodium chloride solution and was dried with anhydrous
Sodium sulfate. Organic layer was concentrated to syrup to obtain 8g of crude
duloxetine free amine.
Example: 3
Preparation of (^)-(+)-N-methvl-3-(naphthalen-l-vloxv)-3-(thiophen-2-yl)propan-
1-amine oxalate
5g of the product of example 2 was dissolved in 50 mL Ethyl acetate. Oxalic acid (2.1
g) was dissolved in acetone (10 mL) and was added to the reaction mass. The
suspension was stirred at 25° C for lh. Mass was filtered and washed with lOmL of
acetone. Duloxetine oxalate solids were dried at 25° C for 16h.
Example: 4
Preparation of (S)-(+)-N-methvl-3-(naphthalen-l-vloxv)-3-(thiophen-2-vl)propan-
1-amine hydrochloride
5g product of example 3 was dissolved in 50mL of water and 5mL of aq NH3 was also
added. Duloxetine free amine was extracted to 30mL of Ethyl acetate. Layers were
separated and the aq layer was once again extracted to 30mL of Ethyl acetate. The

combined organic extract was washed with 30mL of water. The organic layer was
concentrated to syrup to get 3.2g of purified Duloxetine free amine.
3.2 g of the purified free amine was dissolved in a mixture of 48mL of Acetone and 3.2
mL of Ethyl acetate mixed previously in the ratio of lv:15v. l.lmL of Cone. HCl was
added drop wise to the reaction mass. Suspension was stirred at 25° C for 2h. Reaction
mass was filtered to obtain 2 g of Duloxetine Hydrochloride crystals.
Example: 5
Preparation of (S)-(+)-N-methvl-3-(naphthalen-l-vloxv)-3-(thiophen-2-vl)propan-
1-amine hydrochloride
5g of (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine was
dissolved in a mixture of 5mL of Ethyl acetate and 75mL of Acetone at 25° C. 1.7 mL
of Cone. HCl was added drop wise to the reaction mixture and the semisolid suspension
was stirred for 2h at 25° C. Reaction mass was filtered to obtain of 3.1g of Duloxetine
Hydrochloride.

We claim:
1) A process for preparation of (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine hydrochloride, comprising steps of:
a) preparing (S)-(+)-N,N-dimethyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-
yl)propan-l-amine by reacting (S)-(-)-3-(dimethylamino)-l-(thiophen-2-
yl)propan-l-ol and 1-Flouoro Naphthalene in the presence of Potassium
benzoate and NaH at room temperature in an organic solvent;
b) reacting (S)-(+)-N,N-dimethyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine with ethychloroformate in the presence of a base and organic solvent to get (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate;
c) hydrolyzing (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate in Poly Ethylene Glycol-400 or polyethylene glycol-200 with Potassium hydroxide, sodium hydroxide;

d) dissolving hydrolyzed compound from step c in ethyl acetate and reacting with oxalic acid (dissolved in acetone) to get (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine oxalate;
e) (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine prepared by treating (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine oxalate with aqueous ammonia in water and extracted into ethyl acetate; and
f) (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine dissolved in a mixture of ethyl acetate and acetone and treated with HC1 to get (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine hydrochloride.
2) The process as claimed in claim 1, wherein the organic solvent is selecting from a group comprising toluene, dimethyl sulfoxide, ethyl acetate, acetone, xylene, dimethyl acetamide, dimethyl formamide or mixture thereof.

3) The process as claimed in claim 2, wherein the organic solvent is dimethyl sulfoxide.
4) The process as claimed in claim 2, wherein the organic solvent is toluene.
5) The process as claimed in claim 1, wherein base is selected from the group N, N-Diisopropyl ethyl amine, aquous ammonia and triethyl amine, diethyl amine, ethyl amine.
6) The process according to claim 5, wherein the base is N N-Diisopropyl ethyl amine.
7) The process as claimed in claim 1, wherein said room temperature is ranging between 25° C to 30° C.

Dated this 22nd day of December 2009

M. SURESH GUPTA
Of K&S Partners
Attorney for the Applicant