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 NOVEL INTERMEDIATE IN PREPARATION OF
PRAMIPEXOLE AND SALT THEREOF.
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 novel intermediate in preparation of
pramipexole or salt thereof.
The following specification particularly describes the invention and the manner
in which it is to be performed.
4. DESCRIPTION
The present invention provides a novel intermediate for the preparation of pramipexole or salt thereof.

Formula I
Pramipexole of Formula I is chemically (S)-2-amino-4,5,6,7-tetra-hydro-6-(propylamino)benzothiazole and is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease. Pramipexole is commercially available in the form of dihydrochloride salt as monohydrate.

US patent No. 4,886,812 discloses pramipexole or an acid addition salt thereof. The '812 patent further provides various processes for the preparation of pramipexole.
Journal of medical chemistry, 30, 494-498, (1987), describes a process for the preparation of optically pure pramipexole. It also discloses a process for resolution of racemic 2,6-diamino intermediate using L-(+)-tartaric acid as chiral auxiliary. The so obtained single enantiomer precursor is further converted to pramipexole by a two-step reaction, which involves N-acylation and reduction.
PCT patent application No. WO 02/022590 provides a process for preparation of pramipexole which involves reacting 6-substituted 2-amino-4,5,6,7-tetrahydrobenzothiazole with an amine in the presence of a reducing agent. The 6-substituted group may be an alkoxy, alkylenedioxy or an oxo group.
PCT patent application No. WO 02/022591 provides a process for resolution of pramipexole, which involves reacting racemic pramipexole with a acid to form a monobasic acid addition salt which is further converted into the dibasic acid addition salt.
The present inventors have now found a direct and cost-effective process for the preparation of (-) pramipexole or salt thereof wherein the process does not require introduction and removal of a protective group, instead the propionyl group serves as a protective group and a direct precursor for the desired propyl group.
The term "compound of Formula I or acid addition salt thereof in the present invention refers to a compound of Formula I or its monobasic or dibasic acid addition salt. The acid addition salt can be selected from inorganic or organic acid addition salt. The dibasic acid addition salt can be a mixed acid addition salt
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of two different acids. The term also includes hydrates, solvates and enantiomers of compound of Formula I or acid addition salt thereof.
In one of the aspect of the present invention there is provided a process for the preparation of (-) pramipexole or salt thereof wherein the said process comprises of,
a) reacting the compound of Formula II with bromine to get compound of Formula
III which is optionally isolated,
## STR (

)##
b) cyclizing the compound of Formula III with thiourea to get compound of
Formula IV,

c) reducing the compound of Formula IV with a reducing agent to obtain pramipexole or salt thereof,
d) optionally, resolving pramipexole or salt thereof, with chiral auxiliary to get desired isomer.
Yet another aspect of the present invention provides a compound of Formula III as a useful intermediate in synthesis of pramipexol.
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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 N-(3-bromo-4-oxocyclohexy!)propionamide
To the solution of N-(4-oxocyclohexyl)propionamide (5 gm) in glacial acetic acid (20 ml) was added in dropwise manner a solution of bromine (4.5 gm) in acetic acid. There reaction mixture was stirred for about 3 hours at room temperature and concentrated to about two third of its volume under reduced pressure. To this was added a solution of sodium metabisulphite in water and the mass was extracted with dichloromethane (200 ml). The organic layer was washed with water and concentrated to get the title compound. Yield: 7 gm
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WE CLAIM:
1. A process for the preparation of (-) pramipexole or salt thereof wherein the
said process comprises of,
a) reacting the compound of Formula II with bromine to get compound of Formula
III which is optionally isolated,
## STR(

)##
b) cyclizing the compound of Formula III with thiourea to get compound of
Formula IV,
## STR(
)##
c) reducing, the compound of Formula IV with a reducing agent to obtain pramipexole or salt thereof,
d) optionally, resolving pramipexole or salt thereof, with chiral auxiliary to get desired isomer.

2. A process of claim 1 wherein the bromination is carried out in presence of glacial acetic acid.
3. A process of claim 1 wherein compound of Formula III is isolated from the reaction mass.
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4. A process of claim 1 wherein resolution of pramipexole is carried out using a
chiral auxiliary.
5. A process of claim 4 wherein chiral auxiliary is (L)-(+)-tartaric acid.
6. A compound of Formula

## STR(
H

) ##

7. A compound of Formula III as an intermediate in synthesis of pramipexole or salt thereof.

Dated this 28th day of April, 2006

For Wockhardt Limited

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(Mandar Kodgule) Authorized Signatory