PREPARATION OF DULOXETINE AND ITS SALTS

FIELD OF THE INVENTION

The present patent application relates to a process for the preparation of Duloxetine and its salts.

BACKGROUND OF THE INVENTION

Duloxetine hydrochloride is chemically described as (+)-(S)-A^methyl-v-(1-naphthyloxy)-2-tMophenepropylamine hydrochloride and is structurally represented by Formula I.

Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor and is useful in the treatment of depression. Pharmaceutical products containing duloxetine hydrochloride salt as the active ingredient are commercially available in the market under the brand name CYMBALTA™ as capsules containing an equivalent of 20, 30 and 60 mg of duloxetine for oral administration.

U.S. Patent No. 5,023,269 describes (S)-(+)-N-methyl-3-(l-naphtha lenyloxy)-3-(2-thienyl) propanamine oxalate, its related compounds and processes for their preparation.
U.S. patent no. 5,362,886 discloses the process for preparation of Duloxetine HC1 by that includes reacting (S)-(-)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxy propanamine with fluoronapthalene in presence of potassium benzoate and sodium hydride to produce (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine followed by conversion to phosphoric acid salt. The product obtained is further converted to Duloxetine phenylcarbamate by reacting with phenylchloroformate, which is further reacted with sodium hydroxide in dimethylsulfoxide (DMSO) to form Duloxetine followed by reacting with HC1 to form Duloxetine HC1.

DMSO is relatively not a suitable solvent for use in commercial scale as it is not recoverable, it undergoes decomposition at high temperature in the presence of a base and moreover it is an expensive solvent.

Processes. For jpreparation. of Duloxetine, its pharmaceutically acceptable salts and its intermediates have been described in: European Patent No. 457559; International Application Publication Nos. WO 2006/071868, WO 2006/099468, and WO 2004/056795; U.S. Patent Application Publication Nos. 2006/0128791 and 2004/0249170.

Therefore there is a need for a process, which is advantageous in preventing racemization and eco-friendly so as to increase the yields of the final product and also to yield an pure form of Duloxetine and its pharmaceutically acceptable salts.
SUMMARY OF THE INVENTION

In one aspect, the present patent application provides a process for the preparation of

Duloxetine or a pharmaceutically acceptable salt thereof that includes:

a) reacting (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine of Formula II or a salt there of with 1-fluoronapthalene of Formula III in the presence of sodium hydride and potassium 4-methyl benzoate to obtain (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine of Formula IV;

b) reacting (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)
propanamine of Formula IV with phenyl chloroformate to form Duloxetine
phenyl carbamate of compound of Formula V;

c) reacting Duloxetine phenyl carbamate compound of Formula V with
alkali metal hydroxide in C3-C6 alcohol to form Duloxetine; and

d) reacting Duloxetine with a pharmaceutically acceptable acid.

Each step is contemplated separately in this multi-step synthesis.
Even though the above reaction steps are specifically referred to the S-
isomers of compounds of Formulae II, IV and V, it is contemplated separately for the racemic mixtures of the respective compounds as well.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, "Duloxetine" refers to the S-isomer of N-methyl-Y-(1-naphthyloxy)-2-thiophenepropylamine and N-methyl-v-(1-naphthyloxy)-2-thiophenepropylamine referred to as the racemic mixture of S and R isomers.

"Potassium 4-methyl benzoate" that is used in the preset application refers to the potassium salt of 4-methyl benzoic acid which is represented by the following structural formula.

In one aspect, the present patent application provides a process for the preparation of Duloxetine or a pharmaceutically acceptable salt thereof that includes:

a) reacting (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine of Formula II or a salt there of with 1-fluoronapthalene of Formula III in the presence of sodium hydride and potassium 4-methyl benzoate to obtain (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine of Formula IV;

b) reacting (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)
propanamine of Formula IV with phenyl chloroformate to form Duloxetine
phenyl carbamate of compound of Formula V;

c) reacting Duloxetine phenyl carbamate compound of Formula V with alkali metal hydroxide in C3-C6 alcohol to form Duloxetine; and

d) reacting Duloxetine with a pharmaceutically acceptable acid.
Step a) involves reaction of (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine of Formula II or a salt there of with 1 -fluoronapthalene of Formula III.

Suitable solvent that may be used for the reaction of step a) includes polar aprotic solvents such as dimethylformamide(DMF), dimethylacetamide(DMAC), dimethylsulfoxide(DMSO) and the like; aromatic hydrocarbons such as toluene, xylene and the like.

Suitably the reaction is carried out in the presence of a strong base such as sodium hydride.

Suitable temperature for conducting the reaction can range from about 25°C to about reflux temperature of the solvent used, preferably about 40°C to about 80°C. The reaction can be conducted till the completion of the reaction. Typically the reaction time varies from about 1 hour to about 10 hours.

After completion of the reaction, the reaction mixture may be quenched with water and excess base is neutralized with a suitable acid such as acetic acid. The product may be extracted into a suitable organic solvent at a suitable pH such as about 7.5 to about 10 being suitable. Organic layer containing the product may be separated, washed with water and proceed to next step directly or it can be distilled to obtain the product as residue.

Suitable solvent that may be useful for extracting the product includes esters such as ethyl acetate, n-propylacetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like.

In one embodiment, (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine of Formula IV obtained as residue may be purified by using suitable techniques such as isolating as a salt form including phosphate salt.

Step b) involves reacting (S)-(+) N, N-Dimethyl-3~(1-naphthalenyloxy)-3-(2-thienyl) propanamine of Formula IV with phenyl chloroformate to form Duloxetine phenyl carbamate compound of Formula V.

Suitable solvent that may be used for the reaction of step a) includes aromatic hydrocarbon solvents such as toluene, xylene and the like.

If (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine of Formula IV is in the form of an acid addition salt, it may be converted to free base before it is reacted with phenylchloroformate using suitable techniques such as by treating with an aqueous base solution and extracting into an organic solvent followed by distillation.

Suitably the reaction is carried out in the presence of acid scavenger such as triethylamine, diisopropylamine, diisopropylethylamine and the like.

Suitable temperature for conducting the reaction can range from about 25°C to about reflux temperature of the solvent used, preferably about 30°C to about 70°C. The reaction can be conducted till the completion of the reaction. Typically the reaction time varies from about 30 minutes to about 10 hours.

After completion of the reaction, the reaction mixture may be quenched with water and excess phenylchloroformate and acid scavenger removed by washing with basic and acidic water respectively. Organic layer containing the product may be separated, washed with water and proceed to next step directly or it can be distilled to obtain the product as residue.

Step c) involves reacting Duloxetine phenyl carbamate of compound of Formula V with alkali metal hydroxide in G3-C6 alcohol to form Duloxetine;

Suitable C3-C6 alcohols that may be used include isopropanol, 2-butanol, tertiary butanol and the like.

Alkali metal hydroxide that may be used includes lithium hydroxide, sodium hydroxide, and potassium hydroxide.

Alkali metal hydroxide may be used in the form of solid or as a solution obtained by dissolving alkali metal hydroxide in water.

Suitable temperature for conducting the reaction can range from about 50°C to about reflux temperature of the solvent used, preferably reflux temperature of the solvent used.

The reaction can be conducted till the completion of the reaction. Typically the reaction time varies from about 1 hour to about 20 hours.

The molar ratio of compound of Formula V to alkali metal hydroxide can range from about 1:1 to about 1:10.

After completion of the reaction, the reaction mixture may be quenched with ice cold water and excess base is neutralized with a suitable acid such as acetic acid. The product may be extracted into a suitable organic solvent at a suitable pH such as about 8 to about 10 being suitable. Organic layer containing the product may be separated, washed with water and proceeds to next step directly or it can be distilled to obtain the product as residue.

Suitable solvent that may be useful for extracting the product includes esters such as ethyl acetate, n-propylacetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like.

Step d) involves reacting Duloxetine with a pharmaceutically acceptable acid.

Suitable pharmaceutically acceptable acids include hydrobromic acid, hydrochloric acid, and organic acids such as acetic acid, succinic acid, oxalic acid, tartaric acid, formic acid, and maleic acid. Preferable acid is Hydrochloric acid.

Suitable organic solvents that may be used include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol; ketones such as acetone, methyl ispbutyl ketone, methyl ethyl ketone, and n-butanone; esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, and cyclohexane. Mixtures of any of these solvents are also contemplated or their combinations without limitation.

The product obtained may be" further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35° C to about 70° C with or without vacuum. The drying can be carried out for any desired time periods to achieve the desired product purity, time from about 1 to 20 hours frequently being appropriate.

The process described herein is believed to yield substantially pure Duloxetine Hydrochloride.

Even though the above reaction steps are specifically referred to the S-isomers of compounds of Formulae II, IV and V, it is contemplated separately for the racemic mixtures of the respective compounds as well.

In one embodiment N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine or a salt there of is reacted with 1 -fluoro naphthalene in the presence of potassium 4-methyl benzoate and sodium hydride to-yield N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine.

In another embodiment AT-methyl-Y-(1-naphthyloxy)-2-thiophenepropylamine is prepared by reacting N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine with phenyl chloroforamte in the presence of triethylamine to yield corresponding carbamate intermediate, which is then reacted with alkali metal hydroxide in C3-C6 alcohol.

These racemic intermediates may then be converted into Duloxetine or a salt there of using processes including those known in the art.

The process of the present invention is simple and convenient for commercial manufacturing.

Having thus described the invention with reference to particular preferred embodiments and illustrative example, those in the art may appreciatemodification to the invention-.as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set for to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well know to those of ordinary skill in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety.

EXAMPLES

Example 1: Preparation of (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine phosphate 100 gm of (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine is dissolved in DMSO (500 ml) at room temperature. Sodium hydride (23 gm) is added over a period of 1 hour in three equal lots at room temperature and stirred for 1 hour. 10 gm of potassium 4-methyl benzoate as added and stirred for 15 minutes. The reaction mixture was heated to about 55 °C and then 4-fluoronapthalene (100 gm) was added slowly for 45 minutes. The reaction mixture was maintained for 4 hours at about 65 °C. After completion of the reaction, the reaction mass is quenched into ice cold water (600 ml) and pH was adjusted to about 4 with 140 ml of acetic acid. Reaction mixture was washed with pet ether (3 X 100 ml). Aqueous layer was separated and pH adjusted about 8.5 with caustic soda and extracted with ethyl acetate (2 X 200 ml; 1 X 150 ml). The organic layer was washed with saturated aqueous sodium chloride solution (3x200) and further dried with sodium chloride. The organic layer pH was adjusted to about 2 with phosphoric acid and maintain for 30 minutes. The precipitated phosphate salt was filtered and washed with ethyl acetate to obtain 230 gm of the title compound as wet solid.

Example 2: Preparation of Duloxetine phenyl carbamate(Formula V)
100 gm of dry (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3K2-
thienyl) propanamine phosphate was charged In a flask containing i§00 ml
of water and 425[ml of toluene and stirred for 5 minutes 87.5 ml of aqueous
amnionia solution was added and stirred for 10 minutes. Separate the -
aqueous layer and extract with toluene(2 X 250 ml). Total organic layer was-
washed with 10 % aqueous sodium chloride solution (2 X 200 ml) and
further dried with sodium chloride. The organic layer was distilled
completely under vacuum to obtain. 75 gm of freebase.

75 gm of the above obtained freebase was dissolved in toluene (125 ml) and added triethylamine (6.2 gm) and stirred for 15 minutes. A mixture of phenylchloroformate (60 gm) and toluene (65 ml) was added slowly for about 30 minutes at below 50 °C and stirred for about 1 hour. The reaction mixture was cooled to room temperature and washed with 5% aqueous sodium bicarbonate solution (2 X 100 ml). The organic layer was washed with 5% aqueous HC1 solution(2 X 100 ml) followed by with 5% aqueous sodium bicarbonate solution (2 X 100 ml) .The organic layer was washed with 10 % aqueous sodium chloride solution (3 X 100ml) and further dried with sodium chloride. The final organic layer was distilled completely under vacuum to obtain 100 gm of the title compound as residue.

Example 3: Prepration of Duloxetine HC1

100 gm of Duloxetine phenyl carbamate obtained in example-2 was dissolved in isopropanol (500 ml) and stirred for 10 minutes. A mixture of KOH (104 gm) and water (100 ml) solution was added and heated to reflux and stirred for 12 hours. The reaction mixture was quenched into ice cold water (600 ml), adjusted the pH to about 4 with 200 ml of acetic acid and washed with pet ether (3 X 100 ml). Aqueous layer was separated and pH adjusted to about 9 with aqueous ammonia solution (300 ml). The aqueous layer was extracted with toluene (1 X 500; 2 X 200 ml). The organic layer was washed with 10 % aqueous sodium chloride solution (2 X 200ml) and further dried with sodium chloride.

The final organic layer was distilled completely under vacuum to obtain 45 gm of duloxetine free base as residue.

The residue was dissolved in ethyl acetate (200 ml) and cooled t&0 °C, The reaction solution pH was adjusted to about 2 with 16 % isopropyl alcoholic-'HG1(45 ml) slowly and stirred for about 1 hour at 0 to 5 PC. The precipitated solid was filtered and washed with ethyl acetate to get(S)*(+) Duloxetine HG1 (35 gm).

Example 4: Preparation of (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine 25 gm of (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine is dissolved in DMSO (125 ml) at room temperature. Sodium hydride (5.75 gm) is added over a period of 1 hour in three equal lots at room temperature and stirred for 1 hour. 2.5 gm of potassium 4-methyl benzoate was added and stirred for 15 minutes. The reaction mixture was heated to about 55 °C and then 1-fluoronapthalene (25 gm) was added slowly for 45 minutes. The reaction mixture was maintained for 4 hours at about 65 °C. After completion of the reaction, the reaction mass is quenched into ice cold water (150 ml) and pH was adjusted to about 4 with 25 ml of acetic acid. Reaction mixture was washed with pet ether (3 X 25 ml). Aqueous layer was separated and pH adjusted about 8.5 with caustic soda and extracted with ethyl acetate (2 X 50 ml). The organic layer was washed with saturated aqueous sodium chloride solution (3X50 ml) and further dried with sodium chloride. The organic layer was distilled completely under vacuum to give 29 gm of title compound as residue.

Example 5: Preparation of Duloxetine phenyl carbamate:

About 29 gm of (S)-(+) N, N-Dimefhyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine obtained in example 4 was dissolved in toluene (87 ml) and added triethylamine (2.9 gm) and stirred for 15 minutes. A mixture of phenylchloroformate (26 gm) and toluene (29 ml) was added slowly for about 30 minutes at about 50 °C and stirred for about 1 hour.

The reaction mixture was cooled to room temperature and washed with water (250 ml) and 5% aqueous sodium bicarbonate solution (2 X 50 ml). The organic layer was washed with 5% aqueous HC1 solution (2 X 50 ml) followed by with 5% aqueous sodium bicarbonate solution (2 X 50 ml) The organic layer was washed ;with 10 % aqueous sodium chloride solution (3 X 50 ml) and further - dried with sodium-chloride. The^ final organic layer was distilled completely T under vacuum to obtain: 40 gm of the title: compound as residue. Example 6: Preparation of Duloxetine HC1

About 40gm of Duloxetine phenyl carbamate obtained in above example 5 was dissolved in terfc butanol (200 ml) and stirred for 10 minutes. A mixture of KOH (41.2 gm) and water (40 ml) solution was added and heated to reflux and stirred for 12 hours. The reaction mixture was quenched into ice cold water (200 ml), adjusted the pH to about 4 with 70 ml of acetic acid and washed with pet ether (3 X 50 ml). Aqueous layer was separated and pH adjusted to about 9 with aqueous ammonia solution (40 ml). The aqueous layer was extracted with toluene (3 X 100ml). The organic layer was washed with 10 % aqueous sodium chloride solution (2 X 200ml) and further dried with sodium chloride. The final organic layer was distilled completely under vacuum to obtain 29 gm duloxetine free base as residue.

The residue was dissolved in ethyl acetate (90 ml) and cooled to 0 °C. The reaction solution pH was adjusted to about 2.0 with 16 % isopropyl alcoholic HC1 (22 ml) slowly and stirred for about 1 hour at 0 to 5 °C. The precipitated solid was filtered and washed with acetone (150 ml) to get (S)-(+) Duloxetine HC1 (24 gm).

We Claim:

1. A process for preparing Duloxetine or a pharmaceutically acceptable salt thereof comprising reacting Duloxetine phenyl carbamate compound of Formula V with an alkali metal hydroxide in a solvent comprising C3-C6 alcohol.

2. The process of claim 1, further comprising reacting Duloxetine with a pharmaceutically acceptable acid to form a salt. Wherein pharmaceutically acceptable acids are selected from hydrochloric acid and hydrobromic acid

3. The process of claim 1, wherein the alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide.

4. The process of claim 1, wherein C3-C6 alcohol comprises isopropanol, 2-butanol and tertiary butanol.

5. The process of claim 1, wherein the molar ratio of alkali metal hydroxide to Duloxetine phenyl carbamate is from about 1:1 to about 10:1.
6. The process of claim 1, wherein the reaction is conducted at about 50°C to about reflux temperature of the solvent used.

7. The process of claim 1, wherein Duloxetine phenyl carbamate is
prepared by reacting (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-

thienyl) propanamine of Formula IV with phenyl chloroformate in the presence of an acid scavenger.

8. A process for the preparation of (S)-(+) N, N-Dimethyl-3-(l-
naphthalenyloxy)-3-(2-thienyl) propanamine of Formula IV comprising
reacting (S) - (+)-N, N-Dimethyl-3-(2-tWenyl)-3-hydroxypropanamine of
Formula II with 1-fluoronapthalene of Formula III in the presence of sodium
hydride and potassium 4-methyl benzoate.

9. The process of claim 8, wherein the molar ratio of potassium 4-methyl benzoate to (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine of Formula II is from about 0.05:1 to 1:1.

10. The process of claim 8, wherein the reaction is carried out in a solvent comprising dimethylformamide(DMF), dimethylacetamide(DMAC), dimethylsulfoxide(DMSO), toluene and xylene.

11. The process of claim 8, wherein the reaction is carried out at 25°C to about reflux temperature of the solvent used.

12. The process of claim 8, wherein (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine is isolated in the form of a phosphate salt.

13. A process for the preparation of Duloxetine or a pharmaceutically acceptable salt thereof comprising:

a) reacting (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine
of Formula II or a salt there of with 1-fluoronapthalene of Formula III in the
presence of sodium hydride and potassium 4-methyl benzoate

to obtain (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine of Formula IV;

b) reacting (S)-(+) N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)
propanamine of Formula IV with phenyl chloroformate to form Duloxetine
phenyl carbamate of compound of Formula V;


c) reacting Duloxetine phenyl carbamate of compound of Formula V
with alkali metal hydroxide in C3-C6 alcohol to form Duloxetine; and

d) reacting Duloxetine with a pharmaceutically acceptable acid.

14. A process for the preparation of N, N-Dimethyl-3-(1-naphthalenyloxy)-
3-(2-thienyl) propanamine comprising reacting N, N-Dimethyl-3-(2-thienyl)-
3-hydroxypropanamine or a salt there of with 1-fluoro naphthalene in the
presence of potassium 4-methyl benzoate and sodium hydride.

15. A process for the preparation of N-methyl-Y-(1-naphthyloxy)-2-
thiophenepropylamine comprising

a) reacting N, N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)
propanamine with phenyl chloroformate in the presence of triethylamine;

b) reacting the resultant carbamate intermediate with alkali metal
hydroxide in C3-C6 alcohol.