FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
A SINGLE STEP PROCESS FOR THE PREPARATION AND PURIFICATION OF DULOXETINE ACID ADDITION SALT
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process single step process for the preparation and purification of duloxetine acid addition salt.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides a process single step process for the preparation and purification of duloxetine acid addition salt. More particularly present invention is related to preparation and purification of duloxetine hydrochloride.
Duloxetine hydrochloride is chemically known as (+)-(S)-A/-(1-naphthyloxy)-2-thiophenepropylamine-Y-methyl-hydrochloride having structure depicted in Formula I. Duloxetine is indicated for the treatment of major depressive disorder (MDD) and for the management of neuropathic pain associated with diabetic peripheral neuropathy.

Formula I
U.S. Patent No. 5,023,269 disclosed the duloxetine and the pharmaceutically acceptable acid addition salts thereof.
U.S. Patent No. 5,491,243, U.S. Patent No. 6,541,668 and U.S. patent No. 5,362,886 provides the process for the preparation of duloxetine hydrochloride using ethyl acetate and hydrochloric acid.
Other processes of preparation of duloxetine or salt thereof and intermediates useful in the preparation of duloxetine are disclosed in U.S. patent Nos. 5,491,243, 7,119,211, U.S. Patent application Nos. 2004/181058, 2005/171360, 2005/197503, 2005/256318, 2005/272940, 2005/261514, 2006/264641, 2006/05956, 2006/128791, 2006/252945, 2006/194869, 2006/270859, 2006/270860, 2006/258871, 2006/276660, 2006/270731, 2006/270861, 2007/10678 and PCT application Nos. 2005/108386, 2006/27798, 2006/45255, 2006/126213, 2007/06132.cess.
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There is a need in the art for the development of synthetic processes for the preparation of duloxetine hydrochloride that improves purity, yield and cost effective. The present invention provides such processes.
The present inventors have surprisingly found an efficient single step process for the preparation and purification of duloxetine hydrochloride. The process involves converting duloxetine base to duloxetine hydrochloride using dry hydrogen chloride or alcoholic saturated with hydrogen chloride. Further, when the product obtained thereof is washed with organic solvent without isolation, the purity and yield of duloxetine hydrochloride is increased. The present invention is easily scalable at commercial scale and avoids the step of recrystallisation.
In one of the aspect of the present invention there is provided a single step process for the preparation and purification of duloxetine hydrochloride. The process includes steps of,
a) combining duloxetine base with suitable organic solvent
b) treating the solution of step ( a) with dry hydrogen chloride
c) washing the solid mass of step (b) with organic solvent
d) isolating duloxetine hydrochloride from the reaction mass thereof.
In another aspect of the present invention there is provided a single step process for the preparation and purification of duloxetine hydrochloride. The process includes steps of,
a) combining duloxetine base with suitable organic solvent
b) treating the solution of step( a) with alcoholic hydrogen chloride
c) washing the solid mass of step (b) with organic solvent
d) isolating duloxetine hydrochloride from the reaction mass thereof.
The process of present invention is related to a single step preparation of duloxetine hydrochloride in high yield and purity. This involves adding duloxetine base in organic solvent. The resultant solution was then treated with either dry
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hydrogen chloride or alcoholic hydrogen chloride at 0°C to -10°C. The alcohol may be selected from a group comprising one or more of C1-C4 linear chain or branched chain alcohols such as methanol, ethanol, propanol, isopropyl alcohol and the like. The precipitated solid was filtered, washed with organic solvent and isolated. The duloxetine hydrochloride obtained by this process in high yield and has high purity with ( R )- enantiomer of duloxetine base absent.
Organic solvent comprising of aromatic hydrocarbon such as benzene or toluene or the like, C2-8 ether, C3-8 esters, C1-8 straight or branched chain alcohol, acetonitrile and ketone such as acetone, propanone or the like.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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 hydrochloride
Duloxetine base (38.0 gm, HPLC purity 96%) was dissolved in acetone (380.0
ml). The dry hydrogen chloride was purged in to the solution till pH reaches to 1-
2 at 0°C. The reaction mixture was stirred for one hour. The resultant solid was
filtered and washed with fresh acetone (225.0) to get the title product.
Yield: 24.7 gm.
Purity: 99.8 % by HPLC.
Example 2 Preparation of duloxetine hydrochloride
Duloxetine base (25.5 gm, HPLC purity 96%) was dissolved in acetone (400 ml). The isopropyl alcoholic hydrogen chloride (8.3 %) (25 ml) was added drop wise in to the solution till pH reaches to 1-2 at 0° C. The reaction mixture was stirred
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for one hour. The resultant solid was filtered and washed with fresh acetone
(225.0 ml) to get the title product.
Yield: 16.6 gm.
Purity: 99.8 % by HPLC
Example 3 Preparation of duloxetine hydrochloride
Duloxetine base (25.0 gm, HPLC purity 96%) was dissolved in ethyl acetate (250.0 ml). The dry hydrogen chloride was purged in to the solution till pH reaches to 1-2 at 0°C. The reaction mixture was stirred for one hour. The resultant solid was filtered and washed with fresh ethyl acetate (225.0) to get the title product. Yield: 19.0 gm. Purity: 99.8 % by HPLC.
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WE CLAIM:
1. A single step process for the preparation and purification of duloxetine
hydrochloride. The process comprising,
a) combining duloxetine base with suitable organic solvent
b) treating the solution of step (a) with dry hydrogen chloride
c) washing the solid mass of step (b) with organic solvent
d) isolating duloxetine hydrochloride from the reaction mass thereof.

2. A process of claim 1, wherein the organic solvent is selected from the group consisting of aromatic hydrocarbon such as benzene or toluene or the like, C2-8 ether, C3-8 esters, C1-8 straight or branched chain alcohol, acetonitrile and ketone such as acetone, propanone or the like.
3. A process of claim 1, wherein the dry hydrogen chloride is purged in to the solution in an amount sufficient to provide a pH of about 1 to about 5.
4. A process of claim 1, wherein the dry hydrogen chloride is treated at a temperature of 0°C to -10°C.
5. A single step process for the preparation and purification of duloxetine hydrochloride. The process comprising,

a) combining duloxetine base with suitable organic solvent
b) treating the solution of step (a) with alcoholic hydrogen chloride
c) washing the solid mass of step (b) with organic solvent
d) isolating duloxetine hydrochloride from the reaction mass thereof.
6. A process of claim 5, wherein the organic solvent is selected from the group
consisting of aromatic hydrocarbon such as benzene or toluene or the like, C2-8
ether, C3-8 esters, C1-8 straight or branched chain alcohol, acetonitrile and ketone
such as acetone, propanone or the like.
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7. A process of claim 5, wherein the alcoholic hydrogen chloride is added in to the solution in an amount sufficient to provide a pH of about 1 to about 5.
8. A process of claim 5, wherein the dry hydrogen chloride is treated at a temperature of 0°C to -10°C.
9. Duloxetine hydrochloride having the purity 99.8 % or more with the (R)-enantiomer of duloxetine base absent.

Dated this 20TH day of Apr, 2007.
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