The present invention relates to a process for the preparation of duloxetine, its intermediates and salts thereof.
Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRl) for oral administration. It is chemically (+)-(S)-/V-methyl-y-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride as represented by Formula
(Formula Removed)
The processes for the preparation of duloxetine and its intermediates are provided in EP 0,457,559 A3, US 5,362,886, WO 03/062219, WO 03/070720, EP 1,506,965, WO 04/005307, US 2004/0181058, WO 04/056795, WO 04/065376, WO 04/055194, WO 03/018572, JP 2003-192681 A2, US 2003/225153, US 2005/107621, WO 04/005220, WO 04/005239, WO 04/011452, WO 04/013123, WO 04/016603, DE 10237272 A1, WO 04/020389, WO 04/024708, WO 04/031168, EP 1411045 A1, DE 10248479 A1, DE 10248480 A1, WO 04/090094, WO 04/103990, WO 05/021527, WO 05/033094, WO 05/073215, WO 05/080370, US 2003/225274, US 2003/225153, US 2004/023348, US 2004/023344, US 6,924,386, DE 10237272 A1, US 2004/181058.
US Patent No 5,023,269 provides a process for the preparation of racemic duloxetine oxalate and it discloses maleate and oxalate salts of S-(+)-duloxetine. However, the '269 patent does not suggest or provide any method to arrive specific isomers of duloxetine and its salts. Tetrahedron Letters, 31(49), 1990, 7101-7104 provides a process for preparing duloxetine by dealkylating the
oxalate salt of the compound of Formula II. In this process, the final compound of duloxetine is isolated as oxalate or maleate salt.
(Formula Removed)
US Patent No 5,491,243 provides a similar process for preparing for duloxetine, wherein the phosphoric acid salt of the compound of Formula II is used as an intermediate, which is dealkylated to obtain duloxetine. In this process, the final compound of duloxetine is isolated as a hydrochloride salt.
The present inventors have observed that the prior art processes for preparing duloxetine require the isolation and purification of the intermediates at various stages to obtain the final compound. Specifically, the prior art processes involve the isolation of compound of Formula II as a salt of phosphoric acid or oxalic acid.
The present inventors have developed a simple process for the preparation of duloxetine and its salts. The present process does not require the isolation and purification of intermediates. Further, the present invention provides a process for the preparation of duloxetine directly from a free base of the compound of Formula II without compromising yield or purity, and therefore, reduces the processing steps involved in the salt formation and isolation of the compound of Formula II. Thus, the present process is simple, economic and industrially preferable for preparing duloxetine and salts.
A first aspect of the present invention provides a process for the preparation duloxetine of Formula I or its salts thereof,
(Formula Removed)
wherein the said process comprises,
a) reacting (1S)-3-(dimethylamino)-1-(2-thienyl)propan-1-ol of Formula III or its
salts,
(Formula Removed)
with 1-fluoronaphthalene in an organic solvent to obtain (3S)-A/,/V-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propan-1-amine of Formula II or its salts,
(Formula Removed)
b) dealkylating (3S)-N,N-dimethyl-3-(1 -naphthyloxy)-3-(2-thienyl)propan-1 -amine
of Formula II or its salts obtained from step a) to obtain duloxetine of Formula I or
its salts,
c) isolating duloxetine of Formula I or its salts from the reaction mixture thereof,
without isolating the compound of Formula II or its salts from the reaction mixture
in any solid form.
A second aspect of the present invention provides a process for the preparation of duloxetine of Formula I or its salts thereof,
(Formula Removed)
wherein the said process comprises,
a) dealkylating the free base of (3S)-/V,N-dimethyl-3-(1-naphthyloxy)-3-(2-
thienyl)propan-1-amine of Formula II to obtain duloxetine of Formula I or its salts,
(Formula Removed)
b) isolating duloxetine of Formula I or its salts from the reaction mixture thereof.
(1S)-3-(dimethylamino)-1-(2-thienyl)propan-1-ol of Formula III or its salts can be prepared according to the methods provided in US Patent No 5,491,243. This compound is reacted with 1-fluoronaphthalene in the presence of an organic solvent to obtain (3S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propan-1-amine of Formula II or its salts. The organic solvent is selected from a group comprising of dimethylsulfoxide, C1-3 alkanol, toluene, chloroform, dioxane, dimethylformamide, dimethylacetamide, tetrahydrofuran, and related solvents. The compound of Formula II is preferably in the form of free base and it is not required to be isolated from the reaction mixture in any solid form. The compound of Formula II is dealkylated using phenyl chloroformate or 2,2,2-trihaloethylchloroformate. The delakylation process can proceed by the formation of a carbamate intermediate, and it is not required to be isolated from the reaction mixture. The treatment of the carbamate intermediate with a base provides duloxetine. The duloxetine can be isolated from the reaction mixture as
a free base. The salt forms of duloxetine can be isolated by treating the free base of duloxetine with appropriate acid. Preferably duloxetine is isolated as maleate or hydrochloride salt.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF DULOXETINE MALEATE
a) Preparation of 3-dimethylamino-1-(2-thienyl)-1-propanaone
hydrochloride:
A mixture of 2-acetylthiophene (100 g, 0.793 mole), dimethylamine hydrochloride (81.21 g, 0.996 mole), paraformaldehyde (35.36 g) and concentrated hydrochloric acid (3.7 g) in isopropyl alcohol (240 ml) was stirred under reflux for 12 h. The mixture was cooled to 0°-5°C and stirred at the same temperature for 6 h. The solid was filtered, washed with cold (5°-10°C) isopropyl alcohol (100 ml), and dried under vacuum at 45°-50°C for 12 h to obtain the title compound as a white solid.
Yield: 135 g
b) Preparation of 3-dimethylamino-1-(2-thienyl)-1-propanol:
A solution of 1 N sodium hydroxide (460 ml) was added to a mixture of 2-thienyl-2-dimethylaminoethyl ketone hydrochloride (100 g, 0.455 mole) in methanol (350 ml) at about 25°C to the pH of 11. After cooling the reaction mixture to 10°-15°C, sodium borohydride (8.5 g, 0.224 mole) was added in portion over a period of 30 minutes. The reaction mixture was stirred at about 25°C for 2 h. After the completetion of the reaction, excess sodium borohydride was decomposed by addition of acetone at about 25°C. The mixture was stirred at about 25°C for 30
minutes. After concentrating the reaction mixture under reduced pressure to about 1/3 of the initial volume, the concentrated reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (2 x 400 ml). The ethyl acetate layer was washed with water and concentrated under reduced pressure. Hexanes (200 ml) were added to the residue and the mixture was stirred for at about 25°C for 1 h and at 5°-10°C for further 1 h. The solid was filtered and dried under vacuum at 40°-45°C for 4-6 hr to provide the title compound as an off-white solid.
Yield: 78 g
c) Preparation of (S)-N,N-dimethyl-3S-hydroxy-3-(2-thienyl)propanamine •
(S)-(+)-mandelate:
A solution of S-(+)-mandelic acid (34.4 g, 0.226 mole) in absolute ethanol (70 ml) was added to a mixture of racemic dimethylamino alcohol obtained from step b) (70 g, 0.377 mole) in ethyl acetate (630 ml) at 45°-50°C over a period of 25 minutes. The mixture was stirred at 45°-50°C for 1 h and at about 25°C for 12 h. The solid material precipitated out was filtered, washed with ethyl acetate (2 x 70 ml) and dried under vacuum at 55°-60°C for 4-6 h to obtain the title compound as a white solid.
Yield: 58 g
d) Preparation of (S)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine:
A suspension of mandelic acid salt obtained from step c) (58.4 g, 0.173 mole) in water was adjusted to the pH of about 12 by the addition of 1 N sodium hydroxide at about 25°C. The reaction mixture was extracted with toluene (584 ml) and again with toluene (292 ml). After washing with water, toluene layer was concentrated under reduced pressure to obtain the title compound.
e) Preparation of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-
thienyl)propanamine:
Sodium hydride (7.27 g, 0.182 mole) was added to the residue obtained from step d) in dimethyl sulfoxide (122 ml) at 10°-20°C in portion over a period of 30 minutes. The mixture was stirred at about 25°C for 30 minutes. Potassium benzoate (2.77 g, 0.0173 mole) was added to the reaction mixture and stirred at about 25°C for further 30 minutes. A solution of 1-fluoronaphthalene (30.3 g) in dimethyl sulfoxide (61 ml) was added to the reaction mixture at about 25°C. The reaction mixture was stirred at 50°-55°C for 3-4 h. After the completion of the reaction, the reaction mixture was cooled to 10°C and acidified to the pH of 4-4.5 with acetic acid. The reaction mixture was diluted with water (732 ml) and further acidified to the pH of 1.5-2.0 with 6 N hydrochloric acid. The reaction mixture was washed with hexane (2 x 290 ml) at about 25°C. The acidic aqueous layer was adjusted to the pH of about 11 with 30% sodium hydroxide solution and subsequently extracted with ethyl acetate (2 x 584 ml). The ethyl acetate layer was washed with water (2 x 584 ml) and concentrated under reduced pressure to obtain the tile compound as an oily mass.
f) Preparation of (S)-N-methyl-N-phenoxycarbonyl-3-(1-naphthalenyloxy) -3-(2-thienyl)propanamine:
Phenyl chloroformate (30.82 g, 0.196 mole) was added to the mixture of residue obtained from example e) and diisopropylethylamine (4.07 g, 0.0315 mole) in chloroform (497 ml) at 10°-15°C. The reaction mixture was stirred at about 25°C for 2 h. After the completion of the reaction, 1% aqueous sodium bicarbonate solution (584 ml) was added to the reaction mixture and stirred at 45°-50°C for 1 h. The mixture was cooled to about 25°C and the layers were separated. The organic layer was successively washed with 0.5 N hydrochloric acid solution (350 ml), 1% sodium bicarbonate (292 ml) and water (2 x 350 ml). The solvent was evaporated under reduced pressure to obtain the title compound as an oily mass.
g) Preparation of (S)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)
propanaminc:
Pulverized potassium hydroxide (68 g, 1.21 mole) was added to the residue obtained from step f) in toluene (467 ml). The reaction mixture was stirred under reflux for 6 to 8 h. After the completion of the reaction, the reaction mixture was cooled to about 25°C. The solid residue was filtered and washed with toluene (3 x 147 ml). The toluene layer was washed with water (2 x 467 ml) to attain the pH of about 7 to 8 and concentrated under reduced pressure to obtain the title compound as an oily mass.
h) Preparation of duloxetine maleate:
Maleic acid (16.37 g, 0.141 mole) was added to the residue obtained from step g) in ethyl acetate (496 ml) at 40°-45°C. The reaction mixture was stirred at 45°-50°C for 1 h and further at room temperature for 4 h. The solid was filtered, washed with ethyl acetate (2 x 87.5 ml) and dried in air at 45°-50°C for 6 to 8 h to obtain the title compound as a cream colored solid.

WE CLAIM:
1. A process for the preparation duloxetine of Formula I or its salts thereof,
(Formula Removed)
wherein the said process comprises,
a) reacting (1S)-3-(dimethylamino)-1-(2-thienyl)propan-1-ol of Formula III or its
salts,
(Formula Removed)
with 1-fluoronaphthalene in the presence of an organic solvent to obtain (3S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propan-1-amine of Formula II or its salts,
(Formula Removed)
b) dealkylating (3S)-/V,/V-dimethyl-3-(1 -naphthyloxy)-3-(2-thienyl)propan-1 -amine
of Formula II or its salts obtained from step a) to obtain duloxetine of Formula I or
its salts,
isolating duloxetine of Formula I or its salts from the reaction mixture thereof,
without isolating the compound of Formula II or its salts from the reaction mixture
in any solid form.
2. A process as claimed in claim 1, wherein the organic solvent is selected from a
group comprising of dimethylsulfoxide, C1-3 alkanol, toluene, chloroform, dioxane,
dimethylformamide, dimethylacetamide and tetrahydrofuran.
3. A process as claimed in claim 2, wherein the organic solvents is
dimethylsulfoxide or dimethylacetamide.
4. A process as claimed in claim 1, wherein step b) is carried out in the presence
of phenyl chloroformate or 2,2,2-trihaloethylchloroformate.
5. A process as claimed in claim 1, wherein step b) is carried out in the presence
of a base.
6. A process for the preparation of duloxetine of Formula I or its salts thereof,
(Formula Removed)
wherein the said process comprises,
a) dealkylating the free base of (3S)-/V,/V-dimethyl-3-(1-naphthyloxy)-3-(2-
b) isolating duloxetine of Formula I or its salts from the reaction mixture thereof.
thienyl)propan-1-amine of Formula II to obtain duloxetine of Formula I or its salts,
(Formula Removed)
A process as claimed in claim 6, wherein step a) is carried out in the presence
of phenyl chloroformate or 2,2,2-trihaloethylchloroformate.
7. A process as claimed in claim 6, wherein step a) is carried out in the presenceof a base.
8. A process as claimed in claim 6, wherein step b) comprises treating duloxetine
of Formula I with maleic acid or hydrochloric acid.
10. A process as claimed in claim 9, wherein duloxetine of Formula I is isolated
as duloxetine maleate.