FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
AN IMPROVED PROCESS FOR THE PREPARATION OF
PRAMIPEXOLE AND SALTS THEREOF.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana, Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides an improved process for the preparation of pramipexole and salts thereof.
The following specification particularly describes the invention and the manner in which
it is to be performed.


FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Pramipexole and salts thereof.
BACKGROUND OF THE INVENTION
Pramipexole (Formula I) is chemically known as (5)-2-amino-4,5,6,7-tetrahydro-6-(propylamino) benzothiazole and is indicated for treating symptoms of idiopathic Parkinson's disease. Pramipexole is commercially available as dihydrochloride salt monohydrate.

Formula I
U. S. Patent No. 4,886,812 discloses several tetrahydrobenzthiazole compounds including Pramipexole and also various processes for its preparation. The presence of a chiral center in Pramipexole molecule means that it can exist in different stereoisomeric forms. Subsequently, a considerable number of prior art references deal with the separation of individual optical isomers of Pramipexole from the racemic mixture.
For example, U. S. Patent No. 6,727,367 discloses a process for resolving or enriching racemic (R, S) Pramipexole into individual optical isomers using a monovalent salt. A research article published in the Journal of Medical Chemistry (30, 494-498, (1987)) describes a process for the preparation of optically pure Pramipexole. Typically, the process involves resolution of racemic 2,6-diamino intermediate using L-(+)-tartaric acid as chiral auxiliary into individual optical isomers. The single enantiomer precursor so obtained is then converted into Pramipexole by a two-step reaction involving a JV-acylation and reduction.
U. S. Patent No. 6,770,761 is also directed to a process for the preparation of Pramipexole and certain intermediates used in said process.


In general, the prior art reports reaction of S-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with n-propanal in a polar solvent to obtain the Pramipexole free base. However, the product yields are considerably low in this reaction, which makes this synthetic approach commercially less attractive. Additionally, this reaction also results in the formation of the coloring impurities which make the final product appear off-white. Thus, it is highly desirable to have a selective and efficient process for the preparation of Pramipexole. During their efforts to develop such a process, the present inventors have now surprisingly found that when S-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole is reacted with n-propanal in a mixture of a polar organic solvent and water, the product is obtained in high yields. The use of mixed solvent system containing water and polar organic solvent also reduced the formation of impurities. As a result, the color of the product along with its purity improved.
SUMMARY OF THE INVENTION
Accordingly, in one aspect of the present invention, there is provided a process for preparation of Pramipexole or a salt thereof comprising:
(a) reacting 5-(-)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with w-propanal in a mixture of water and at least one polar organic solvent,
(b) treating reaction mass obtained in step (a) with a reducing agent,
(c) isolating pure Pramipexole base from the reaction mass obtained in step (b), and optionally
(d) converting Pramipexole free base into its salt.
Typically, the polar organic solvent is selected from alcohols, N,N-dimethylformamide, tetrahydrofuran, dioxane or a mixture thereof.
Preferably, the alcohol is a C1-C6 alcohol or a mixture of C1-C6 alcohols.
Still preferably, the alcohol is selected from methanol, ethanol, propanol, isopropanol or a mixture thereof.


Typically, the reducing agent is selected from borate, aluminate or acetate hydrides of alkaline metals or alkaline earth metals.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparation of Pramipexole or a salt thereof comprising:
(a) reacting