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:
AN IMPOROVED PROCESS FOR THE 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 process for the preparation 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 process for the preparation of (-) pramipexole or salt thereof.

Formula I
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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 of two different acids. The term also includes hydrates, solvates and enantiomers of compound of Formula I or acid addition salt thereof.
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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) cyclizing the compound of Formula II with bromine and thio urea to obtain
compound of Formula IV

b) reducing the compound of Formula IV with a reducing agent to obtain pramipexole or salt thereof,
c) 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 II as a useful intermediate in synthesis of pramipexol.
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.
3

EXAMPLE 1
Preparation of 2-amino-4,5,6,7- tetrahydro-(6-propionamido) benzothiazole:
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 thiourea (4.5 gm) was added. The reaction mixture was refluxed for 1 hour and cooled to room temperature, basified with sodium hydroxide solution (5N) and extracted in chloroform (100 x 3). The chloroform extract was dried and concentrated to give title compound as yellow solid. Yield: 6 gm
EXAMPLE 2
Preparation of racemic pramipexole
To the ice cooled solution of sodium borohydride (6.4 gm) in tetrahydrofuran (30 ml) was added 2-amino-4,5,6,7-tetrahydro-(6-propionamido)benzothiazole (5.4 gm) in one lot. To this stirred suspension was added boron trifluoride etherate (21 ml) in drop-wise manner. The reaction mixture brought to 20°C in an hour then heated to 48-50°C for 4-8 hours. After completion of the reaction, reaction mixture was cooled to 0°C and quenched with hydrochloric acid, basified with sodium hydroxide solution (20%) and the separated product filtered, washed with water and dried to get title compound. Yield: 2.8 gm
4

EXAMPLE 3
Preparation of (S)-Pramipexole
To the methanolic solution of racemic pramipexole (6 gm) was added L-(+) tartaric acid (4.8 gm) under stirring. The mixture was cooled and the separated product was filtered washed with methanol and dried.
The dried product was added to chilled water and to this mixture was added concentrated hydrochloric acid. To the clear solution in acid was added aqueous potassium hydroxide till pH was sufficiently alkaline. The separated product was filtered washed and dried to get title compound as white solid. Yield: 2.8 gm. HPLC Purity: 99.5%
5

WE CLAIM:
1. A process for the preparation of (-) pramipexole or salt thereof wherein the
said process comprises of,
a) cyclizing the compound of Formula II with bromine and thiourea to obtain
compound of Formula IV

b) reducing the compound of Formula IV with a reducing agent to obtain pramipexole or salt thereof,
c) optionally, resolving pramipexole or salt thereof, with chiral auxiliary to get desired isomer.

2. A process of claim 1 wherein the cyclization is carried out in presence of glacial acetic acid.
3. A process of claim 1 wherein the reducing agent comprises of sodium borohydride, boron trifluride etherate or mixture thereof.
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

6. A compound of Formula II.

7. A compound of Formula II 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