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 PROCESS OF 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 process for preparation of 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 novel 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.

Formula I
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.
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PCT patent application No. WO 02/022591 provides a process for resolution of pramipexole, which involves reacting racemic pramipexole with an 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. It also excluded the reduction stage to get 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 acid addition or I 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 V or salt thereof with propylating agent to get compound of Formula VI salt thereof

Formula V
Formula VI
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b) oxidizing the compound of formula VI to get compound of formula VII

Formula VII
c) reacting the compound of Formula VII with thiourea in presence of bromine to get pramipexole or salt thereof, which is optionally , resolved to get desired isomer.
Yet another 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) oxidizing the compound of Formula V to get compound of Formula VIII

Formula V

Formula VIII

b) reacting the compound of Formula VIII or salt thereof with propylating agents to get compound of Formula VII or salt thereof

Formula VII

c) reacting the compound of Formula VII with thiourea in presence of bromine to get to get pramipexole or salt thereof, which is optionally , resolved to get desired isomer.
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The compound of formula V and VIII are propylated using different propylating agents. The propylating agent can be selected from a compound of formula CH3-CH2-CH2-X wherein X is leaving group such as tosylate, mesylate or halide; to get the compound of formula VI and VII. The reaction can be carried out in presence of aqueous organic solvent such as C1-4 alcohols like methanol, ethanol, propanol or a like or mixture of solvent under reflux condition. The desired compound is obtained by removing solvent under vacuum.
The Compound of formula V or VI are subjected to oxidation in aqueous media with oxidizing agent like Pyridinium chloro Chromate( PCC), Jone's reagent or the like. The desired compound is extracted in suitable organic solvent after basification of reaction moisture. The solvent is evaporated under vacuum to yield compounds of formula VII or VIII.
Cyclization reaction is carried out in glacial acetic acid at lower temperature by adding bromine to the solution of compound VII followed by addition of thiourea. The desired precipitated product is filtered, washed with acetone and dried. The racemic product can then be resolve by dissolving in suitable aqueous organic solvent in presence of chiral auxiliary like L (+) tartaric acid. The desired enantiomer of pramipexpol can then be converted to its suitable salt such as dihydrochloride salt by purging of hydrogen chloride gas through the solution of product in ethanol by conventional method known in the art.
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.
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EXAMPLE 1
Preparation of N-(4-aminopropyl) cyclohexanol Para toluene sulphonic acid salt
Trans-4-aminocyclohexanol (20 gm) was dissolved in methanol and propypyl tosylate (37.2 gm) was added to the reaction mixture. The reaction mixture was heated to reflux for 5-8 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum to get the solid, which was suspended in cold methanol and filtered to get the tilted compound as white solid. Yield: 45.16 gm
EXAMPLE 2
Preparation of N- (4-aminopropyl) cyclohexanone
The N- (4-aminopropyl) cyclohexanol para toluene sulphonic acid (5 gm) was dissolved in water (50 ml). The reaction mixture was cooled to 0 to 10°C and concentrated sulphuric acid was added drop wise followed by potassium dichromate (4.46 gm) in portions. The reaction mixture was stirred at room temperature for 4-6 hour and after completion it was basified and extracted in dichloromethane. Dichloromethane was concentrated to yield the titled compound. Yield: 1.32 gm
EXAMPLE 3
Preparation of 4- amino cyclohexanone
The 4-amino cyclohexanol (1 g) was taken in water (25 ml) and cooled to 0-10°C. The concentrated sulphuric acid was added (2.64 ml) drop wise to the reaction
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mixture followed by K2Cr2C>7 in portions. Reaction mixture was stirred at room temperature for 4-6 hours for completion. After completion of the reaction, the reaction mixture was basified and extracted in dichloromethane. The dichloromethane was evaporated under reduced pressure to yield the titled compound. Yield: 0.4 gm
EXAMPLE 4
Preparation of N- (4-aminopropyl) cyclohexanone Para toluene sulphonic acid salt
The 4-amino cyclohexanone (0.3 gm) was taken in aqueous I PA (10% water, 25 ml) and to it, was added propyl tosylate (0.568 gm).The reaction mixture was refluxed for 4-8 hours. After completion of the reaction the solid obtained was filtered and dried to yield the titled compound. Yield: 0.32 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 V or salt thereof with propylating agent to get compound of Formula VI salt thereof


HO—( )—NH

Formula V


HO-< )—N'

Formula VI
b) oxidizing the compound of formula VI to get compound of formula VII

Formula VII

c) reacting the compound of Formula VII with thiourea in presence of bromine to get pramipexole or salt thereof, which is optionally, resolved to get desired isomer.
2. A process for the preparation of pramipexole or salt thereof wherein the said process comprises of,
a) oxidizing the compound of Formula V to get compound of Formula VIII
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b) reacting the compound of Formula VIII or salt thereof with propylating agents to
get compound of Formula VII or salt thereof

H
Formula VII
c) reacting the compound of Formula VII with thiourea in presence of bromine to
get to get pramipexole or salt thereof, which is optionally , resolved to get desired
isomer.
3. A process of claim 1 or 2 wherein the propylating agent is propyl tosylate.
4. A compound of Formula VI


HO—( y- N

Formula VI
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5. A compound of Formula VII

Formula VII

Dated this 28th day of June, 2006

For Wockhardt Limited
(Dr. Yatendra Kumar) Authorized Signatory

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