PREPARATION OF DULOXETINE, ITS SALTS AND INTERMEDIATES THEREOF

FIELD OF THE INVENTION

The present patent application relates to an improved process for the preparation of Duloxetine, its salts and intermediates thereof.

BACKGROUND OF THE INVENTION

Duloxetine hydrochloride is chemically described as (+)-(S)-iV-methyl-Y-(l-naphthyloxy)-2-thiophenepropylamine 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 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-(l-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.

Our co-pending PCT application no PCT/IN2009/000028 discloses a process for preparation of Duloxetine HC1, which overcomes some of the disadvantages of reported processes.

Processes for preparation 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 racemizations, minimization of impurity formation and eco-friendly so as to increase the yields of the final product and also to yield pure form of Duloxetine and its pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION

The present patent application relates a process for the preparation of Duloxetine or a pharmaceutically acceptable salt thereof that includes:

a) reacting (S)-(+) N, N-Dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)
propanamine of Formula II with alkyl or aryl chloroformate in an aliphatic
hydrocarbon solvent medium to form Duloxetine carbamate of Formula III;
Wherein R is an alkyl or aryl group

b) reacting Duloxetine carbamate of Formula III with alkali metal
hydroxide in C3-C6 alcohol to form Duloxetine of Formula IV; and

c) reacting Duloxetine with a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt.

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

DETAILED DESCRIPTION OF THE INVENTION

The present patent application relates a process for the preparation of Duloxetine or a pharmaceutically acceptable salt thereof that includes:

a) reacting (S)-(+) N, N-Dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine of Formula II with alkyl or aryl chloroformate in an aliphatic hydrocarbon solvent medium to form Duloxetine carbamate of Formula III;

b) reacting Duloxetine carbamate of Formula III with alkali metal hydroxide in C3-C6 alcohol to form Duloxetine of Formula IV; and

c) reacting Duloxetine with a pharmaceutically acceptable acid to form a pharmaceutically acceptable salt.

Step a) involves reacting (S)-(+) N, N-Dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine of Formula II with alkyl or aryl chloroformate to form Duloxetine carbamate compound of Formula III.

Aliphatic hydrocarbon solvent that may be used for the reaction of step a) includes C5 to CIO straight chain, branched or cyclic hydrocarbons having boiling point between 40 and 100 °C. Examples include n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane and the like or mixtures thereof. Preferable solvent is cyclohexane.

Suitable alkyl or aryl chloroformate includes ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate, phenyl chloroformate and the like.

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

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 of alkyl or aryl chloroformate and acid scavengers are removed by washing the organic layer with basic and acidic water respectively. The organic layer containing the product may be separated, washed with water and preceded to next step directly or it can be distilled to obtain the product as residue.

Most of the processes reported in the literature involve use of toluene as solvent medium for the reaction, which is finally after work up distilled under vacuum at high temperature to recover the product. It has been observed that the purity and yield of the product is getting affected due to the high temperature of the toluene organic layer distillation. The present application involves use of solvents having low boiling temperature to avoid formation of impurity.

In one embodiment, organic layer containing the product is directly used in the process of next reaction, in which the solvent is removed by distillation.

Step b) involves reacting Duloxetine carbamate of Formula III with alkali metal hydroxide in C3-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.

In one embodiment, alkali metal hydroxide is added to the organic layer containing
Duloxetine carbamate of Formula III followed by complete distillation of the aliphatic hydrocarbon solvent. C3-C6 alcohol is then added to the reaction mixture.

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 III 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 c) involves reacting Duloxetine with a pharmaceutically acceptable acid to form a salt.

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 isobutyl 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 I, II, III and IV, it is contemplated separately for the R-isomer or racemic mixtures of the respective compounds as well.

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 appreciate modification 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 Duloxetine phenyl carbamate: 70.5 gm of (S)-(+) N, N-Dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine was dissolved in cyclohexane (212 ml) and triethylamine (7 gm) was added and stirred for 15 minutes. A mixture of phenylchloroformate (63.5 gm) and cyclohexane (50 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 (200 ml) and 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 70 ml) and further dried with sodium chloride to get 310 ml of cyclohexane layer containing Duloxetine phenyl carbamate.

Example 2: Preparation of Duloxetine HC1

310 ml of cyclohexane layer containing Duloxetine phenyl carbamate obtained in Example 1 was added to a mixture of KOH (107 gm) and water (107 ml). The cyclohexane was distilled off completely at below 75°C and then cooled the reaction mixture to 68°C. 430 ml of t-butanol was added to the reaction mixture, heated to reflux and maintain for 6 hours. After completion of the reaction (checked by Thin layer chromatography), the t-butanol solvent was distilled off completely and added water (300 ml) was added to the reaction mixture. The aqueous layer was extracted with toluene (IX 150 ml, IX 100ml and IX 50 ml). The organic layer was washed with 10 % aqueous sodium chloride solution (150ml) and further dried with sodium chloride. The final organic layer was distilled completely under vacuum to obtain 68 gm Duloxetine free base as residue.

The obtained residue was dissolved in ethyl acetate (250 ml) and cooled to 10-15 °C. The reaction solution pH was adjusted to about 2.0 with 16 % isopropyl alcoholic HC1 (35 ml) slowly and stirred for about 1 hour at 0 to 5 °C. The precipitated solid was filtered and washed with acetone (200 ml) to get 38 gm of Duloxetine HC1.

We claim:

1. A process for preparing Duloxetine or a pharmaceutically acceptable salt thereof comprising:

a) the reaction of (S)-(+) N, N-Dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine of Formula II with alkyl or aryl chloroformate to form Duloxetine carbamate compound of Formula III in presence of acid scavenger and solvents selected from the non polar hydrocarbon like cyclohexane, hexane, heptane and pentane.

b) Basifying the non polar hydrocarbon solvent layer containing Duloxetine carbamate compound of Formula III with an alkali metal hydroxide in water and then the non polar hydrocarbon solvent layer was distilled out completely to get compound of Formula III.

c) Reacting the compound of Formula III with alkali metal hydroxides in the presence of a solvent comprising C3-C6 alcohol to obtain Duloxetine of formula IV and converting into its pharmaceutically acceptable salts thereof.

2. The process of claim 1 step a), wherein the alkyl or aryl chloroformate was selected from phenyl chloroformate, ethyl chloroformate, isopropyl chloroformate and tert-butyl chloroformate.

3. The process of claim 1 step a), wherein the acid scavenger was selected from triethylamine, diisopropylamine and diisopropylethylamine

4. The process of claim 1 step a), wherein the reaction is carried at 0°C to about reflux temperature of the solvent used.

5. The process of claim 1 step a), wherein the mole ratio of alkyl or aryl chloroformate to (S)-(+) N, N-Dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine of Formula II is about 0.5:1 mole to 2:1 moles.

6. The process of claim 1 step b), wherein the non polar hydrocarbon solvent layer containing Duloxetine carbamate compound of Formula III was basified with alkali metal hydroxide dissolved in water.

7. The process of claim 1 step b), wherein the non polar hydrocarbon solvent layer was distilled out completely to obtain compound of Formula III

8. The process of claim 1 step b), wherein the alkali metal hydroxides are selected from potassium hydroxide, sodium hydroxide and lithium hydroxide.

9. The process of claim 1 step C), wherein the solvent C3-C4 alcohols are selected from t-butanol, n-butanol and isopropyl alcohol and alkali metal hydroxides are selected from potassium hydroxide, sodium hydroxide and lithium hydroxide.

10. The process of claim 1 step c), wherein the pharmaceutically acceptable salts is Hydrochloric acid.