FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A PROCESS FOR PREPARING FLUOXETINE HYDROCHLORIDE
(FORM-A)
2. APPLICANT (S)
(a) NAME: Wockhardt Limited
(b) NATIONALITY: Indian
(c) ADDRESS:
Wockhardt Towers,
Bandra-Kurla Complex,
Bandra (East),
Mumbai-400051,
India
3. PREAMBLE TO THE DESCRIPTION A process for the preparation of an anti-depressent Fluoxetine Hydrochloride Form-A and also synthesis of a novel group of intermediate to be used in the process is described.
The following specification particularly describes the invention and the manner in which it
is to be performed.
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4. FIELD OF THE INVENTION
A process for the preparation of an anti-depressent Fluoxetine Hydrochloride Form-A and also synthesis of a novel group of intermediate to be used in the process is described.
BACKGROUND OF THE INVENTION
Fluoxetine is an anti-depressent drug that is known by its chemical name as N-methyl-3-[(4-trifluoromethyl) phenoxy]-3-phenylpropylamine.It has the following structural formula:

Fluoxetine hydrochloride Form-A is a well-known anti-depressent drug .Its pharmacological effect is based on its ability to be a potent and selective brain serotonin re-uptake inhibitor without any influence on the dopamine and norepinephrine systems.Process for the preparation of Fluoxetine is disclosed in U.S. Patent No. 4,314,081 in which fluoxetine is prepared by using cyanogenbromide, a toxic and hazardous substance .U.S. Patent No. 5,166,437 describes esterification of l-phenyl-3-N-methyl aminopropane-1-ol with p-chlorobenzotrifluoride in the presence of potassium-t-butoxide to give Fluoxetine. U.S. Patent No. 5,225,585 discloses O-alkylation of 3-methylamino-1-phenyl-1-propanol with p-chlorobenzotrifluoride to give Fluoxetine base which when treated with hydrochloride gas forms crude Fluoxetine hydrochloride.
SUMMARY OF THE INVENTION
The present invention discusses a process for the preparation of Fluoxetine Hydrochloride Form-A of Formula I. The invention discusses the preparation of 3-methylamino-1-phenylpropanol, which comprises reacting 3-chloro propionylchloride (II) with benzene in
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presence of anhydrous aluminium chloride to give 3-chloro-l-phenyl-1-oxopropane (III). Reduction of 3-chloro-l-phenyl-l-oxo-propane in an alcoholic solvent gives 3-chloro-l-phenyl-1-propanol (IV). Reaction of methylamine (aqueous) with 3-chloro-1-phenyl-1-propanol using phase transfer catalyst gives 3-methylamino-l-phenylpropanol (V) . O-alkylation of 3-methylamino-1-phenylpropanol (V) with p-chlorobenzotrifluoride formed Fluoxetine which was extracted with toluene and treated with hydrochloric acid to furnish semi pure Fluoxetine Hydrochloride which was purified further.
The Fluoxetine Hydrochloride Form-A is characterized by IR and from XRD peaks.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an IR spectrum of Fluoxetine Hydrochloride Form-A.
Figure 2 is an X-Ray Diffraction Pattern (XRD) of Fluoxetine Hydrochloride Form-A.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed towards an efficient process for the preparation of N-methyl-3- [(4-trifluoromethyl) phenoxy]-3-phenylpropylamine (Fluoxetine Hydrochloride Form-A).
The present invention provides a novel form of Fluoxetine hydrochloride preferably Fluoxetine Hydrochloride Form-A. Following methods were employed for the preparation of Fluoxetine Hydrochloride Form-A:
3-Chloro propionylchloride (II) is treated with benzene in the presence of a catalyst that includes, but are not limited to boron trifluoride, anhydrous aluminium chloride etc., preferably anhydrous aluminium chloride to give 3-chloro-1-phenyl-1-oxopropane (III). Selective reduction of 3-chloro-l-phenyl-1-oxo-propane using sodium borohydride in an alcoholic solvent like ethanol, methanol, isopropanol, more preferably isopropanol gives 3-chloro-l-phenyl-1-propanol (IV). Reaction of an amine that includes, but not limited to ethyl amine, propyl amine.methylamine etc., preferably methyl amine (aqueous) with 3-chloro-l-phenyl-1-propanol
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using phase transfer catalyst like tetrabutylammonium iodide, tetrabutylammonium bromide etc., preferably tetrabutylammonium iodide between a temperature range of 30 to 70°C, more preferably 50 to 60°C gives 3-methylamino-l-phenylpropanol (V).
O-Alkylation of 3-methylamino-l-phenylpropanol (V) with p-chlorobenzotrifluoride formed Fluoxetine which was extracted with xylene,toluene etc., preferably toluene and treated with hydrochloric acid to produce semi pure Fluoxetine Hydrochloride has an HPLC Assay of 97.5%. The crude Fluoxetine Hydrochloride is purified by using an alcohol that includes, but not limited to ethanol, methanol, isopropanol, more preferably isopropanol.
The purified Fluoxetine Hydrochloride Form-A is characterized from XRD peaks and has an HPLC Assay of 99.45%.
The Infra Red (IR) spectrum pattern characterizes Form-A of Fluoxetine Hydrochloride that includes the peaks at about 2959, 2791, 2732, 2450, 1615, 1588, 1517, 1473, 1426, 1330, 1244,1164,1109, 1070,1045, 958, 844, 765, 700 and 645 cm-1 as shown in Figure 1.
The X-Ray diffractogram pattern expressed in terms of angles (2 , degrees) of Fluoxetine Hydrochloride Form A that includes the peak at about 5.5, 10.12, 13.200, 13.860, 14.540, 16.440, 17.920, 18.240, 18.540, 18.900, 19.220, 20.280, 20.760, 21.980, 22.860, 23.760, 24.300, 24.760, 25.240, 25.540, 25.740, 26.560, 27.140, 27.580, 27.940, 28.900, 31.860, 32.580, 34.480, 34.880 and 35.440 as shown in Figure 2.
Fluoxetine Hydrochloride Form-A as prepared in this invention endotherm appears in the temperature range of about 154 to 160°C.
The following examples illustrate the invention, but are not limiting thereof.
EXAMPLE 1
Preparation of N-methyl-3-[(4-triluoromethyl)phenoxy]-3-phenylpropylamine hydrochloride (Fluoxetine Hydrochloride)
Following methods describe the preparation of Fluoxetine Hydrochloride .
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Preparation o f3-Methylamino-l-phenylpropanol (V)
a) 3-Chloro-l-phenyl-1-oxo-propane (III)
Benzene (2.5 Litre) was cooled to 15°C and to it anhydrous aluminium chloride (725 gm, 5.43 mole) was added in lot wise and the reaction mixture was cooled to 4°C and 3-chloropropionylchloride (625 gm, 6.98 mole) was added drop wise in duration of 2 hours, keeping the temperature below 4°C. Maintained the reaction mixture for 6 hours. After the reaction was over, reaction mixture was poured into ice (3.50 Kg) and water (3.5 Litre) and stirred and the organic layer was separated. The organic layer thus obtained was washed with water (4 X 3.0 Ltr) to get pH almost neutral. The weight of organic layer 2.45 Kg, which is taken was such for the next stage.
b) 3-Chloro-l-phenyl-l-oxo-propanol (IV)
Isopropyl alcohol (1.75 Ltr) was charged into organic layer of a) above and then sodium borohydride (92.5 gm) was added in portion below 5°C and stirred for 4 to 6 hours. After completion of reaction, acidified with sulfuric acid (150 gm) and diluted with water (1.50 Ltr). The organic layer was separated and washed with water (3 X 1.5 Ltr) to get pH 6.8 to 7.2. Solvent was distilled out under vacuum below 55 to 60°C to get oily mass (740 gm) which is used in the next stage as such.
c) 3-Methylamino-I-phenylpropanol (V)
To a stirred solution of aqueous monomethylamine (5.80 Kg) and tetrabutylammonium iodide (12.50 gm) charged 3-chloro-1 -phenyl- 1-oxo-propanol (IV) at room temperature. Heated 50 to 60°C for 15 to 20 hours. After completion of reaction, water was distilled out under vacuum (30 to 40 mm/Hg). The brown coloured oily residue thus obtained was diluted with water (2.0 Litre) and lye (500 gm). The aqueous layer was extracted with toluene (2 X 1.5 Litre) and finally with 1.0 Litre toluene. Combined toluene extract was distilled out below 110°C under vacuum. Crude 3-methylamino-l-phenylpropanol (628 gm) thus obtained was purified by
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high vacuum distillation (1 to 2 mm/Hg) to get pure 3-methylamino-l-phenylpropanol (510 gm). Assay by HPLC = 94.75%, Melting Point = 62.8°C.
EXAMPLE 2
Preparation of N-methyl-3-[(4-triluoromethyl)phenoxy]-3-phenylpropylamine hydrochloride (Fluoxetine Hydrochloride)
3-Methylamino-l-phenylpropanol (500 gm), dimethylsulfoxide (750 ml) were charged to toluene (800 ml). Toluene (~200 ml) was recovered under vacuum at 45 to 60°C and the reaction mixture was cooled. Sodium hydride (200 gm, 60%) was added in portion between 15 to 35°C and then slowly heated to 50 to 55°C. The reaction mixture so obtained was further stirred for about 1 hour at 50 to 55°C and maintained for 8 to 10 hours. After the completion of reaction, cooled to room temperature and ethyl acetate (70 ml) was added to destroy sodium hydride if present. Water (1.0 Litre) and toluene (4.0 Litre) were added and the organic layer was separated. The toluene extract was charcoalized and filtered. Filtrate was cooled to 2 to 3°C and concentrated hydrochloric acid (274 gm) was added to get pH = 3.0. The solid crude Fluoxetine hydrochloride was filtered. Wet weight of crude Fluoxetine hydrochloride (954 gm) which was suspended in toluene (1.90 Litre) and heated to 40°C and then cooled to 0 to 2°C, filtered and dried in vacuum oven at 45 to 50°C to get semi pure Fluoxetine hydrochloride (654 gm). Assay by HPLC = 97.5%.
Purification of semi pure Fluoxetine hydrochloride (Form-A)
Semi pure Fluoxetine hydrochloride (652 gm) was taken in isopropyl alcohol (6.52 Ltr) and heated at 40 to 43 °C to make a clear solution, which was charcoalized and filtered. Clear filtrate was cooled to 0 to 5°C, filtered and dried in vacuum oven below 50°C to get pure Fluoxetine hydrochloride (512 gm). Assay by HPLC = 99.45% and XRD graph showed Form-A.
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We Claim:
1 Fluoxetine Hydrochloride Form-A of the formula I
2 A pharmaceutical composition comprising compound of Formula I.
3 Fluoxetine Hydrochloride Form-A as claimed in claim 1 characterised by an X-Ray Diffraction (XRD) having the following peaks at about 5.5, 10.12, 13.200, 13.860, 14.540, 16.440, 17.920, 18.240, 18.540, 18.900, 19.220, 20.280, 20.760, 21.980, 22.860, 23.760, 24.300, 24.760, 25.240, 25.540, 25.740, 26.560, 27.140, 27.580, 27.940, 28.900, 31.860, 32.580, 34.480, 34.880 and 35.440 and 645 cm-1.
4 Fluoxetine Hydrochloride Form-A as claimed in claim 1 characterised by an IR spectrum.
5 Fluoxetine Hydrochloride Form-A as claimed in claim 1 characterised by a DSC endotherm.
6 Fluoxetine Hydrochloride Form-A as claimed in claim 5 wherein the DSC endotherm appears in the temperature range of about 154 to 160°C.
7 A process for the preparation of compound of Formula I comprising of the following steps:

(a) Treating 3-chloro propionyl chloride (II) with benzene in the presence of a catalyst to form 3-chloro-l-phenyl-l-oxopropane (III).
(b) Selective reduction of 3-chloro-l-phenyl-l-oxopropane (III) in an alcoholic solvent to form 3-chloro-1-phenyl-1-propanol.
(c) Reacting 3-chloro-1-phenyl-1-propanol with an amine using a catalyst to form 3-methylamino-1-phenylpropanol (V).
(d) Reacting 3-methylamino-l-phenylpropanol (V) with p-chlorobenzotrifluoride in a solvent and a base to form Fluoxetine.
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(e) Fluoxetine formed as in step (d) is extracted with an organic solvent.
(f) The extract of step (e) is acidified with hydrochloric acid to give Fluoxetine hydrochloride.
(g) Purification of Fluoxetine hydrochloride in an alcohol.

8 The process of claim 7, wherein the catalyst used in step (a) is boron trifluoride, anhydrous aluminium chloride.
9 The process of claim 8, wherein the catalyst is anhydrous aluminium chloride.
10 The process of claim 7, wherein the said catalyst in step (c) is sodium borohydride.
11 The process of claim 7, wherein the said alcohol used in step (b) is methanol, ethanol, propanol and isopropanol.
12 The process of claim 11, wherein the preferable alcohol is isopropanol.
13 The process of claim 7, wherein the said amine in step (c) is methyl amine, ethyl
amine, propyl amine.
13 The process of claim 13, wherein the said amine is methyl amine.
14 The process of claim 7, wherein the said catalyst used in step (c) is tetrabutylammonium iodide, tetrabutylammonium bromide.
15 The process of claim 14, wherein the catalyst is tetrabutylammonium iodide.
16 The process of claim 7, wherein the said solvent used in step (d) is dimethylsulfoxide
17 The process of claim 7, wherein the said base used in step (d) is sodium hydride.
18 The process of claim 7, wherein the said organic solvent used in step (e) is xylene, toluene.
19 The process of claim 18, wherein the organic solvent is toluene.
20 The process of claim 7, wherein the said alcohol used in step (g) is ethanol, methanol, propanol, isopropanol.
21 The process of claim 20, wherein the alcohol is isopropanol.
22 The process of claim 7, wherein the temperature range in step (d) is from about 85°C to about 100°C.
23 The process of claim 7, wherein the temperature range in step (e) is from 1 to 7°C.
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