DESC:FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of duloxetine.

BACKGROUND OF THE INVENTION:
The chemical name of duloxetine is (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (1).

Duloxetine was disclosed in U.S. patent No. 4,956,388 and its acid addition salts in U.S.patent No. 5,362,886. Duloxetine is a serotonin and norepinephrine re-uptake dual inhibitor and a highly efficient antidepressant agent for treating psychiatric disorders. Its hydrochloride salt is marketed under the brand name Cymbalta® in USA.

Various processes for the synthesis of duloxetine were disclosed in the prior art (US 7560573 US 8269023) which involves the resolution of the intermediates such as follows.

The process of the present invention is advantageous over the prior art processes since it does not involve resolution of any intermediate.

SUMMARY OF THE INVENTION:
The present invention relates to a process for the preparation of duloxetine or pharmaceutically acceptable salt thereof comprising
a) reacting 2-acetyl thiophene (4) with (S)-N-methyl-1-phenylethylamine HCl (5) and formaldehyde source

to get compound of formula 6 or salt thereof

b) reacting compound of formula 6 or salt thereof with suitable reducing agent to get compound of formula 7 or salt thereof

The present invention further relates to a process of converting compound of formula 7 to duloxetine or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION:
In one embodiment there is provided a process for the preparation of duloxetine or pharmaceutically acceptable salt thereof comprising
a) reacting 2-acetyl thiophene (4) with (S)-N-methyl-1-phenylethylamine HCl (5) and formaldehyde source

to get compound of formula 6 or salt thereof

b) reducing compound of formula 6 or salt thereof with suitable reducing agent to get compound of formula 7 or salt thereof
.

In another embodiment compound of formula 6 is optionally converted to its salt.

In another embodiment compound of formula 7 is optionally converted to its salt.

In yet another embodiment the process of the present invention further comprises
c) condensing compound of formula 7 with 1-halonaphthalene to get compound of formula 8 or salt thereof

d) debenzylating compound of formula 8 with suitable reagent to get duloxetine and
e) optionally converting the duloxetine to its pharmaceutically acceptable salt.

In yet another embodiment the process of the present invention further comprises
f) debenzylating compound of formula 7 with suitable reagent to get the compound of formula 9 or salt thereof

g) condensing compound of formula 9 with 1-halonaphthalene to get duloxetine and
h) optionally converting the duloxetine to its pharmaceutically acceptable salt.

In another embodiment compound of formula 8 is optionally converted to its salt.

In another embodiment there is provided a compound of formula 6 or salt thereof
.

In another embodiment there is provided a compound of formula 7 or salt thereof
.
In another embodiment there is provided a compound of formula 8 or salt thereof

According to the present invention ‘salt’ means any acid addition salt including inorganic or organic salt. Inorganic salt may be but not limited to hydrochloride, sulfate or the like. Organic salt may be but not limited to monocarboxylic such as acetate, or dicarboxylic salt such as oxalate or the like. The preferable salt is oxalate.

According to the present invention ‘pharmaceutically acceptable salt’ means Berge, Stephen, M., et al; Review Article: Pharmaceutical Salts; Journal of Pharmaceutical Sciences (1977) vol. 66, No. 1 pp. 1-19. Pharmaceutically acceptable salt is preferably hydrochloride.

‘Formaldehyde source’ can be selected from formaldehyde, paraformaldehyde.

Reducing agent can be selected from potassium borohydride, sodium borohydride and the like.
‘1-halonaphthalene’ is selected from 1-fluoronaphthalene, 1-bromonaphthalene, 1-iodonaphthalene.
Condensation with 1-halonaphthalene may be carried out in presence of alkali amide such as sodium amide or alkali hydroxide such as potassium hydroxide in a suitable solvent such as dimethylsulfoxide.

Debenzylation can be carried out in presence of Pd(C)/H2 ¬in a suitable alcohol solvent such as methanol or ethanol.

Debenzylation can be carried out by reacting with chloroformate reagent followed by hydrolysis of the carbamate intermediate with alkali hydroxide such as potassium hydroxide in a suitable solvent such as dimethylsulfoxide.

‘Chloroformate’ may be selected from methyl chloroformate, ethyl chloroformate, benzyl chloroformate or the like.

The compound of formula 6 or 7 or 8 may be purified by converting the compound of formula 6 or 7 or 8 into inorganic or organic acid addition salt, isolating the said salt and basifying the said salt to obtain the compound of formula 6 or 7 or 8 in a pure form.

The compounds isolated in the present process may be purified by chromatographic or crystallization techniques.

The present invention is described in the following example, however it should be noted that the scope of present invention is not limited by the examples.

Example 1
Preparation of compound of formula 6

Mixture of 2-acetylthiophene (13g, 0.103 mol), (S)-N-methyl-1-phenylethylamine HCl (19.5 g, 0.113 mol), parafomaldehyde (4.25g, 0.14 mol) and conc. HCl (13 ml) in aqueous ethanol (25 %, 130 ml) was heated at 75-85 °C for 24 hours. Water (100 ml) and diethyl ether (150 ml) were added. The mixture was basified with sodium bicarbonate to pH 8. The organic layer was separated and concentrated to obtain compound of formula 6. Yield 16.65 g,
1H-NMR (CDCl3) d: 1.43-1.45 (3H, d), 2.32 (3H, s), 2.83-3.03 (2H, m), 3.09-3.12 (2H, t), 3.65-3.70 (1H, q), 7.14-7.16 1H, t), 7.66-7.68 (2H, dd), 7.27-7.35 (5H, m).
Mass: m/z 274 (M + 1)+.

Example 2
Preparation of compound of formula 6a

The compound of formula 6 (15 g, 0.054 mol) is dissolved in isopropanol (15 ml) and oxalic acid (5.8 g, 0.064 mol) was added. The mixture was heated at 50-55 °C for 10 min. The mixture was cooled and the solid was isolated. Yield – 14 g. melting point 115.8-116.9 °C.
1H-NMR (DMSO) d: 1.56-1.58 (3H, d), 2.55 (3H, s), 3.11-3.24 (2H, m), 3.42-3.46 (2H, t), 4.37-4.42 (1H, q), 7.99-8.04 (2H, dd), 7.26-7.28 (1H, t), 7.39-7.53 (5H, m), 9.53 (2H, bs).
Mass: m/z 274 (M + 1)+.

Example 3
Preparation of compound of formula 7

Compound of formula 6 (1 g, 0.0036 mol) was added in methanol (7.5 ml). A solution of sodium borohydride (0.20 g, 0.00528 mol) in aqueous sodium hydroxide (1.5 %, 3 ml) was added slowly at about 0 °C. The mixture was stirred at 5°C to 10 °C for 4 hours. The mixture was acidified to pH 2 with aq. HCl (20 %). Water (25 ml) was added and extracted with ethyl acetate (2 X 15 ml). The aqueous layer was basified to pH 8 with aq. sodium bicarbonate solution (6 %) and extracted with ethyl acetate (3 X 15 ml). The organic layer was concentrated to obtain compound of formula 7 as oil. Yield 0.9 g,
IR: Broad peak at 3398.9 (-OH)
1H-NMR (DMSO) d: 1.26-1.27 (3H, d), 1.79-1.85 (2H, m), 2.07 (3H, s), 2.41-2.44 (2H, t), 3.56-3.60 (1H, q), 4.79-4.80 (1H, d), 5.74 (1H, Exchangeable –OH), 6.86-6.92 (2H, dd), 7.22-7.35 (6H, m).
Mass: m/z 276.05 (M + 1)+.

Example 4
Preparation of compound of formula 7

Compound of formula 6a (1.5 g, 0.0041 mol) was added in methanol (17 ml). A solution of sodium hydroxide (0.35 g in 3.5 ml water) was added slowly at about 0 °C. A mixture of sodium borohydride (0.20 g, 0.00528 mol), sodium hydroxide (0.025 g) in water (1.5 ml) was added slowly at about 0 °C. The mixture was stirred at 5°C to 10 °C for 4 hours. The mixture was acidified to pH 2 with aq. HCl (20 %). Water (15 ml) was added and extracted with ethyl acetate (3 X 10 ml). The aqueous layer was basified to pH 8 with aq. sodium bicarbonate solution (6 %) and extracted with ethyl acetate (3 X 20 ml). The organic layer was concentrated to obtain compound of formula 7 as oil. Yield 0.7 g,

Example 5
Preparation of compound of formula 8

Mixture of compound of formula 7 (2.0 g, 0.0072 mol), 1-fluoronaphthalene (1.16 g, 0.0079 mol) and potassium hydroxide (3.6 g, 0.064 mol) in dimethyl sulfoxide (20 ml) was heated at 70-75 °C for 22 hours. The reaction mixture was cooled and added to the cold water (300 ml). The mixture was extracted with cyclohexane (3 X 100 ml). The organic layer was concentrated to obtain the residue which was purified by silica gel column chromatography (60-120 mesh) using 2-7 % ethyl acetate in hexane as mobile phase. The compound of formula 8 is obtained as oil. Yield 1.04 g,
1H-NMR (DMSO) d: 1.18-1.19 (3H, d), 2.12 (3H, s), 2.26-2.41 (2H, m), 2.62-2.65 (2H, t), 3.51-3.53 (1H, q), 5.87 (1H, s), 6.93-8.10 (15H, m).
Mass: m/z 402.35 (M + 1)+.

Example 6
Preparation of duloxetine (1)
Compound of formula 8 (0.25 g, 0.0006 mol) was dissolved in toluene (6 ml) and diisiopropylethylamine (0.1 g) was added followed by phenylchloroformate (0.146 g). The solution was heated at 50-55 °C for 2 hours. The reaction mass was cooled, basified with 2% sodium bicarbonate solution (4 ml) and the organic layer was separated. Organic layer was washed with water and concentrated to get oily mass of carbamate intermdiate. This carbamate intermdiate was dissolved in dimethyl sulfoxide (2 ml) followed by addition of sodium hydroxide solution (0.19 g in 1 ml water). The mixture was stirred at 95 °C for 3 hours and then cooled to 10-15 °C. The mixture was added to cold water (20 ml) and the pH was adjusted to 4.4 with acetic acid. The mixture was extracted with cyclohexane (3 x 5 ml), combined organic layer was washed with water and concentrated to get duloxetine (1) as oily mass. Yield: 0.13 g.

Example 7
Preparation of compound of formula 9

Compound of formula 7 (0.5 g, 0.0018 mol) was dissolved in acetonitrile (5 ml) and triethylamine (0.28 g) was added followed by phenylchloroformate (1.05 g). The solution was stirred at 25-30 °C for 2 hours. The reaction mass was basified with 2% sodium hydroxide solution (18 ml), the lower layer was separated and concentrated to get oily mass of carbamate intermdiate. Potassium hydroxide solution in methanol (8 ml, 24 %) was added to the carbamate intermdiate and the mixture was refluxed for 3 hours. The mixture was concentrated and toluene (5 ml) was added to the residue. The mixture was filtered, concentrated and the residue was washed with n-heptane to obtain compound of formula 9 as oil.

Example 8
Preparation of duloxetine (1)
Duloxetine (1) was prepared from compound of formula 9 by the method as described in Wheeler, William J.; Kuo, Fengjiun; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 36 (3); (1995); p. 213 – 223 and US 7538232.

Example 9
Preparation of hydrochloride salt of duloxetine (1)
Hydrochloride salt of duloxetine (1) was prepared by the method as described in US 8269023.
,CLAIMS:1. A process for the preparation of duloxetine or pharmaceutically acceptable salt thereof comprising
a) reacting 2-acetyl thiophene (4) with (S)-N-methyl-1-phenylethylamine HCl (5) and formaldehyde source

to get compound of formula 6 or salt thereof

b) reacting compound of formula 6 or salt thereof with suitable reducing agent to get compound of formula 7 or salt thereof
.
2. The process as claimed in claim 1 wherein formaldehyde source is selected from formaldehyde and paraformaldehyde.

3. The process as claimed in claim 1 wherein reducing agent is selected from potassium borohydride and sodium borohydride.

4. The process as claimed in claim 1 further comprises
c) condensing compound of formula 7 with 1-halonaphthalene to get compound of formula 8 or salt thereof

d) debenzylating compound of formula 8 with suitable reagent to get duloxetine and
e) optionally converting the duloxetine to its pharmaceutically acceptable salt.

5. The process as claimed in claim 1 wherein 1-halonaphthalene is selected from 1-fluoronaphthalene, 1-bromonaphthalene and 1-iodonaphthalene.

6. The process as claimed in claim 1 further comprises
f) debenzylating compound of formula 7 with suitable reagent to get the compound of formula 9 or salt thereof

g) condensing compound of formula 9 with 1-halonaphthalene to get duloxetine and
h) optionally converting the duloxetine to its pharmaceutically acceptable salt.

7. The process as claimed in claim 1 wherein the pharmaceutically acceptable salt is hydrochloride salt.

8. A compound of formula 6 or salt thereof
.
9. A compound of formula 7 or salt thereof
.

10. A compound of formula 8 or salt thereof
.