FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Duloxetine of Formula I.

BACKGROUND OF THE INVENTION

Duloxetine is chemically known as (+)-(5)~N-methyl-y-(l-naphthyloxy)-2-thiophenepropylamine. Duloxetine is a selective Serotonin and norepinephrine reuptake inhibitor (SSNRI). Although the exact mechanism of the antidepressant, central pain inhibitory and anxiolytic actions of Duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the Central Nervous System (CNS). Duloxetine hydrochloride is used for the treatment of Major Depressive Disorder (MDD), and is marketed under the trade name Cymbalta®.
US Patent No. 5,023,269 disclosed Duloxetine and its pharmaceutically acceptable salts.

According to US '269 Duloxetine can be prepared by condensing (15)-3-(dimethylamino)-l-(thiophene-2-yl)propan-l-ol (II) with 1-fluoronaphthalene in presence of sodium hydride in dimethyl acetamide followed by treating with oxalic acid to produce oxalate salt of N-methyl Duloxetine (III), which is dealkylated using phenyl choroformate in toluene and treating the resulting intermediate (IV) with NaOH to produce Duloxetine (I). The process is as shown in Scheme-I below:

US 5,362,886 discloses a process for the preparation of Duloxetine by condensing (liS)-3-(dimethylamino)-l-(thiophene-2-yl)propan-l-ol (II) with 1-fluoronaphthalene in the presence of sodium hydride and potassium compound in organic solvent to produce N-methyl Duloxetine (III), which is dealkylated using phenyl chloroformate in toluene and treating the resulting intermediate compound (IV) with ammonium hydroxide to produce Duloxetine (I), which is finally converted to Duloxetine hydrochloride (la) by treating with cone. HC1.

The process is as shown in Scheme-II below:

The major disadvantage with the above prior-art processes is the use of dimethyl intermediate compound (III), which involves additional steps of de-alkylation and hydrolysis to produce Duloxetine. In the chemical synthesis, the number of steps are not advisable for the commercialization of the product. The number of steps are more in a chemical process means the lowering of the overall yield and the time cycle of the production is more. This does not make the suitable chemical process.

US 6,541,668 discloses a process for the preparation of Duloxetine by condensing (l>S)-3-(methylamino)-l-(thiophene-2-yl)propan-l-ol (V) with 1-fluoronaphthalene in presence of alkoxide in l,3-dimethyl-2-imidazolidinone or N-methylpyrrolidone to produce Duloxetine (I). The process is as shown in Scheme-Ill below:

SCHEME III

The major disadvantage with the above process is the long process time, low product yields, and the use of hazardous solvents that are incompatible with large-scale industrial synthesis. The alkoxides are very strong bases and therefore are hazardous that brings limitation on their use on large scale.

US 7,538,232 discloses a process for the preparation of Duloxetine HC1 by condensing (lS)-3-(methylamino)-l-(thiophene-2-yl)propan-l-ol (V) with 1 -fluoronaphthalene in the presence of KOH in a mixture of DMSO and toluene to produce Duloxetine (I). The process is as shown in Scheme-IV below:

The major disadvantage of the above process is the use of mixed organic solvents is unfavorable to meet the developing trends of environmental protection. Further, the use of different types of organic solvents in the process for the preparation of Duloxetine increases the overall cost of finished product.

However, there is always a need for alternative preparative routes, which for example, involve fewer steps, use reagents that are less expensive and / or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.

Hence, there is a need to develop cost effective and commercially viable process for the preparation of Duloxetine (I).

The present invention is directed towards the condensation of (lS)-3-(methylamino)-l-(thiophene-2-yl)propan-l-ol (V) with 1-fluoronaphthalene in presence of a base, a solvent and a catalyst for less consumption of the more expensive thiophene starting material and involves short periods of time, easy work-up and high purity to produce Duloxetine (I).

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and cost-effective process for the preparation of Duloxetine hydrochloride (I) with high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the preparation of Duloxetine (I), which comprises: (i) condensing (1 S)-3 -(methylamino)-1 -(thiophene-2-yl)propan-1 -ol (V), with 1-fluoronaphthalene in presence of a base, a solvent and a catalyst to produce Duloxetine (I); (ii) optionally, Duloxetine (I) obtained in step-(i) is converted to Duloxetine hydrochloride (la).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Duloxetine hydrochloride of formula (I).

The process comprises, (lS)-3-(methylamino)-l-(thiophene-2-yl)propan-l-ol (V) is condensed with 1 -fluoronaphthalene using a base selected from alkali hydrides such as sodium hydride, potassium hydride, lithium hydride; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; alkoxide such as sodium methoxide, sodium t-butoxide, sodium ethoxide, potassium t-butoxide, potassium methoxide, potassium ethoxide, lithium ethoxide, lithium t-butoxide, lithium methoxide, magnesium methoxide, magnesium ethoxide, magnesium t-butoxide, a solvent selected from polar aprotic solvent such as tetrahydrofuran (THF), acetone, ethyl acetate, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMT) or mixtures thereof; in the presence of a catalyst selected from potassium compound such as potassium benzoate, potassium acetate to produce Duloxetine (I).

The reaction is carried out at a temperature of about 10 to 80°C, preferably 30 to 60°C for a period of about 2 to 20 hrs, preferably 2 to 6 hrs. After completion of the reaction an acid selected from carboxylic acid such as acetic acid is added to the reaction mass, then quenched the reaction mixture with water and washed with hydrocarbon solvent such as hexanes, heptanes, cyclohexane; then pHof the aqueous layer is basified using a base selected from aqueous sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, followed by extraction, washing and concentration under reduced pressure to produce Duloxetine base.

Duloxetine (I) obtained by the above process is reacted with hydrochloride in a solvent selected from ethyl acetate to produce Duloxetine hydrochloride (la). This salt preparation is preferably carried out at a temperature of 0-25°C.

Duloxetine hydrochloride (la) is purified by known methods, for example by dissolving in a solvent selected from methanol, ethanol, isopropanol, ethyl acetate or mixtures
thereof and precipitating pure Duloxetine hydrochloride by cooling the solution to about 0 to -30°C, or by adding an anti solvent.

(15)-3-(Methylamino)-l-(thiophene-2-yl)propan-l-ol (V) used in the present invention is prepared by the methods reported in the prior-art, preferably by asymmetric hydrogenation of 3-methylamino-l-thiophenepropan-l-one hydrochloride (VI) using hydrogen gas, a base selected form sodium carbonate, potassium carbonate in a solvent selected from methanol, ethanol, isopropanol in the presence of a catalyst selected from transition metal catalyst such as Rh-DuanPhos to produce (15)-3-(methylamino)-l-(thiophene-2-yl)propan-l-ol (V).

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.

EXAMPLES

Example: 1

Preparation of (iS)-(+)-Ar-methyI-y-(l-naphthyIoxy)-2-thiophene propylamine
hydrochloride (Duloxetine hydrochloride crude)

(lS)-3-(Methylamino)-l-(thiophene-2-yl)propan-l-ol (25 g, 0.146 mole) was dissolved in dimethylsulfoxide (90 ml) at 25-30°C under nitrogen atmosphere. Sodium hydride (7.3 g, ~60w/w, 0.183 mole) followed by potassium benzoate (2.8 g, 0.0175 mole) were added to the solution at 25-30°C and stirred for 20 min. The reaction mass was heated to 35-37°C and 1-fluoronaphthalene (25.6 g, 0.175 mole) was added. Thereafter, the reaction mass was heated to 45-50°C and stirred for 21h for completion of the reaction. Acetic acid (26.31 g) was added to the reaction mass, then quenched with DM water (200 ml) and washed with hexanes (2x125 ml) at 20-25°C, then pH of the aqueous layer was adjusted to 10-10.5 with 20% w/w aqueous sodium hydroxide solution (77.48 g) and extracted with ethyl acetate (250 ml and 2x125 ml) at 25-30°C. The combined ethyl acetate layer was washed with 30% w/v aqueous sodium chloride solution (2x125 ml) and concentrated under reduced pressure to yield syrupy mass of Duloxetine base.

The concentrated mass was dissolved in ethyl acetate (422 ml) under nitrogen atmosphere and cooled to 0-5°C. Ethyl acetate-hydrochloride solution (15.8% w/w, 31 g) was added and pH was adjusted to 5.4 at 5-10°C. The resulting slurry was stirred for 1 h at 0-5°C, filtered the product, washed with chilled ethyl acetate (25 ml) and dried at 45-50°C under reduced pressure. Yield: 43 g; Chiral Purity: 99.07%; HPLC Purity: 99.74%.

Purification of (S)-(+)-N-methyI-Y-(l-naphthyloxy)-2-thiophene propylamine hydrochloride (Duloxetine hydrochloride)

Duloxetine hydrochloride crude (20 g) was dissolved in absolute alcohol (60 ml) and the resulting solution was treated with activated carbon (1 g) at 57-60°C for 30 min, then filtered through the hyflo bed and washed with ethanol (20 ml). The filtrate was cooled to -20°C and stirred for 2 h. The product was filtered, washed with chilled ethanol (10 ml) and dried at 50-55°C under reduced pressure. Yield: 17.4 g; HPLC Purity: 99.91%; Chiral Purity: 99.92%.

Example: 2

Preparation of (5)-(+)-N-methyl-y-(l-naphthyloxy)-2-thiophene propylamine hydrochloride (Duloxetine HC1, Crude)

To the solution of sodium hydroxide (29.23 g; 0.73 mole) in dimethylsulfoxide (125 ml), (lS)-3-(methylamino)-l-(thiophene-2-yl)propan-l-ol (25 g, 0.146 mole), potassium benzoate (2.34 g;0.0146 mole), 1 -fluoronaphthalene (32.05 g;0.219 mole) were added at 45-50°C and stirred for 44 h for completion of reaction. Thereafter, the reaction mass was quenched with DM water (200 ml), neutralized with concentrated hydrochloric acid, pH was adjusted to 5.30 with acetic acid (22 g) and washed with hexanes (2x125 ml). The aqueous layer was basified with aqueous sodium hydroxide solution (20% w/w 58.7 g) and extracted with ethyl acetate (2x125 ml) at 20-30°C. The combined ethyl acetate layer was washed with 30% w/v aqueous sodium chloride solution (2x125 ml) at 25-30°C and concentrated under reduced pressure to yield syrupy mass of Duloxetine base. The concentrated mass was dissolved in ethyl acetate (370 ml) under nitrogen atmosphere and cooled to 0-5°C, then ethyl acetate-hydrochloride solution (15.8% w/w 27.37g; 0.118 mole) was added to the solution and pH was adjusted to 5.2 at 5-10°C. The resulting slurry was stirred for lh at 0-5°C. The product was filtered, washed with chilled ethyl acetate (25 ml) and dried at 45-50°C under reduced pressure. Yield: 33.3 g; HPLC Purity: 99.66%; Chiral Purity: 99.67%.

Purification of (5)-(+)-N-methyl-γ-(l-naphthyIoxy)-2-thiophene propylamine hydrochloride (Duloxetine hydrochloride)

Duloxetine hydrochloride crude (15 g) was dissolved in absolute alcohol (45 ml) at 57-60°C, then treated with activated carbon (0.75 g) for 30 min, filtered through the hyflo bed and washed with ethanol (15 ml). The filtrate was cooled to 0-5°C and stirred for 1 h.

The product was filtered, washed with chilled ethanol (7 ml) and dried at 50-55°C under reduced pressure. Yield: 11.86g; HPLC Purity: 99.85%; Chiral Purity: 99.98%.

WE CLAIM:

1. a process for the preparation of Duloxetine (I), which comprises: (i) condensing (1 S)-3 -(methylamino)-1 -(thiophene-2-yl)propan-1 -ol (V), with 1-fluoronaphthalene in presence of a base, a solvent and a catalyst to produce Duloxetine (I); (ii) optionally, Duloxetine (I) obtained in step-(i) is converted to Duloxetine hydrochloride (la).

2. The process according to claim 1, wherein the base used in step-(i) comprises alkali hydrides; alkali or alkaline earth metal hydroxides; alkali or alkaline earth metal alkoxide or mixtures thereof.

3. The process according to claim 2, wherein alkali hydrides comprises sodium hydride, potassium hydride, lithium hydride or mixtures thereof.

4. The process according to claim 2, wherein alkali or alkaline earth metal hydroxides comprises sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide or mixtures thereof

5. The process according to claim 2, wherein alkali or alkaline earth metal alkoxides comprises sodium methoxide, sodium t-butoxide, sodium ethoxide, potassium t-butoxide, potassium methoxide, potassium ethoxide, lithium ethoxide, lithium t-

butoxide, lithium methoxide, magnesium methoxide, magnesium ethoxide, magnesium t-butoxide or mixtures thereof.

6. The process according to claim 1, wherein the solvent used in step-(i) comprises polar aprotic solvent.

7. The process according to claim 6, wherein the polar aprotic solvent comprises tetrahydrofuran (THF), acetone, ethyl acetate, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMT) or mixtures thereof.

8. The process according to claim 1, wherein the catalyst used in step-(i) comprises potassium compound.

9. The process according to claim 8, wherein the potassium compound comprises potassium benzoate, potassium acetate or mixtures thereof.

10. The process according to claim 1, wherein step-(ii) Duloxetine (I) is reacted with hydrochloride in a solvent comprises ethylacetate to produce Duloxetine hydrochloride (la).