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 PROCESS FOR THE PREPARATION OF PRAMIPEXOLE AND SALT THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kuria 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.
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4. DESCRIPTION
The present invention provides a process for the preparation of pramipexole or salt thereof.
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
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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 resolution is performed in the intermediate stage followed by propylation to get the desired isomer of the pramipexole. It excluded the reduction step from the preparation of Pramipexole.
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.
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, alkylating the compound of Formula X with a propylating agent to obtain pramipexole or salt thereof

Yet another aspect of the present invention provides a process for the preparation of pramipexole or salt thereof wherein the said process comprises of,
a) hydrolyzing the compound of Formula IV to get compound of Formula X
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b) alkylating the compound of Formula X with a propylating agent to obtain pramipexole or salt thereof and if necessary, resolving pramipexol to get the desired isomer or the salt thereof.
The amino group in 4-aminocyclohexanol is protected by propionic anhydride in tetrahydrofuran in presence of triethylamine at lower temperature -10°C to 5°C to get 2-amino-4,5,6,7- tetra hydro (6-propionamido)-benzothiazole by the method known in a prior art. Which is hydrolyzed with aq hydrogen halide under reflux condition to obtain racemic 2, 6 diamino-4,5,6,7- tetrahydrobenzothiazole.
In one of the embodiments the racemic 2, 6 diamino-4,5,6,7-tetrahydrobenzothiazole is resolved using- L- (+) tartaric acid in methanol followed by basification of the desired tartrate salt to get desired isomer. The desired enantiomer is then subjected to propylating agent such as propyl tosylate, propyl mesylate or propyl halide to produce pramipexol or salt thereof.
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In another embodiment the racemic 2, 6 diamino-4,5,6,7-tetrahydrobenzothiazole is first reacted with propylating agent to produce pramipexol or salt thereof which is then resolved to desired enantiomer or salt thereof.
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 2, 6 diamino-4,5,6,7- tetrahydro benzothiazole
The 2-amino-4, 5,6,7- tetra hydro (4-propionamido)-benzothiazole (5 gm) was refluxed with 47% aq HBr (6.6 times w/v) for 7-12 hours. The reaction after completion concentrated partially under vacuum to precipitate the solid which was filtered, dissolved in water and basified with 5N NaOH to give solid which was filtered and dried to give white crystalline titled product. Yield: 4 gm
EXAMPLE 2
Preparation of (S) - 2, 6 diamino-4,5,6,7- tetrahydro benzothiazole
The product of example 1 (2.5 gm) was dissolved in methanol followed by I (+) tartaric acid is added. The reaction mixture was cooled to 0-5°C stirred for 30-45 minutes for the complete precipitation. The precipitated product was filtered dissolved in water (5 ml) HCI, solution is cooled to 0-5°C and basified with aqueous KOH. The reaction mixture was stirred for 30-60 minutes to yield the titled product as a white crystalline solid. Yield: 1.12 gm
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EXAMPLE 3
Preparation of (S)-2-amino-6-propylamino 4,5,6,7- tetrahydro benzothiazole
The (-) 2-amino-6-propylamino 4,5,6,7- tetrahydro benzothiazole (1 gm) was taken in methanol (12.5 ml). The propyl tosylate (1.27gm) was added to reaction mixture and refluxed for 4-8 hour. After completion the reaction mixture was concentrated under reduced pressure the residue obtained was dissolved in water (5ml) and basified with 5N NaOH Solution (8ml) under cool condition 0-10 °C. The precipitated product is filtered and dried to get titled product as white crystalline material. Yield: 0.9 gm
EXAMPLE 4
Preparation of (S) - Pramipexole dihydrochloride.
The product of Example 3 was dissolved in ethanol (5ml) and cooled to 0° C. The dry hydrogen chloride is bubbled through the reaction mixture under stirring for one hour. The precipitated solid was filtered, washed with cold ethanol and dried to yield title compound. Yield: 1.1 gm
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WE CLAIM:
1. A process for the preparation of pramipexole or salt thereof wherein the said process comprises of, alkylating the compound of Formula X with a propylating agent to obtain pramipexole or salt thereof

2. A process for the preparation of pramipexole or salt thereof or salt thereof wherein the said process comprises of,


a) hydrolyzing the compound of Formula IV to get compound of Formula X
b) alkylating the compound of Formula X with a propylating agent to obtain pramipexole or salt thereof and if necessary, resolving pramipexol to get the desired isomer or the salt thereof.
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3. A process of claim 1or 2 wherein the propylating agent is tosylate, propyl mesylate or propyl halide.
4. A process of claim 1 or 2 wherein resolution of pramipexole is carried out using
a chiral auxiliary.
5. A process of claim 4 wherein chiral auxiliary is (L)-(+)-tartaric acid.
Dated this 28TH day of June, 2006

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