FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule!3)
1. TITLE OF THE INVENTION:
A NOVEL INTERMEDIATE FOR SYNTHESIS 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 DESCRD7TION
The present invention relates to 2-bromo-4-aminocyclohexanone, and to their application in the synthesis 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 relates to 2-bromo-4-aminocyclohexanone, and to their application in the synthesis 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.
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 found 2-bromo-4-aminocyclohexanone as a novel intermediate for the preparation of (-) pramipexole or salt thereof wherein the resolution is performed in the intermediate stage followed by propylation or the resolution is performed after the propylation step to get the desired isomer of the 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 aspect of the present invention there is provided a 2-bromo-4-aminocyclonexanone compound of Formula III.

Formula III
In another aspect there is provided a compound of Formula III, as an intermediate in synthesis of pramipexole or salt thereof.
In yet another aspect there is provided a process for the preparation of 2-bromo-4-aminocyclohexanone The process includes the steps of:
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a) brominating the compound of Formula II, in glacial acetic acid,
H2N ^^"^
Formula II
b) extracting 2-bromo-4-aminocyclohexanone of formula III in water immiscible
solvent from the reaction mixture thereof.

Formula III
Bromination reaction can be carried out in glacial acetic acid. The product can be extracted from reaction mass using a suitable water immiscble solvent. The water immiscble solvent can be selected from ethyl acetate, chloroform, cyclohexane, diethyl ether, toluene, hexane, halogenated solvent and the like.
In yet another aspect there is provided a process for the preparation of pramipexole from the 2-bromo-4-aminocyclohexanone intermediate of formula III. The process includes the steps of:
a) cyclizing the compound of Formula III, with a thiourea to obtain
tetrahydrobenzothiazole of formula IV.
s^
Formula IV
b) resolving compound of Formula IV, with chiral auxiliary to get desired
isomer of formula V.
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^-J3^""""NH2
s Formula V
c) reacting the compound of Formula V, with propylating agent in C1-4 alcohols to get pramipexole
In yet another aspect there is provided a process for the preparation of pramipexole from the 2-bromo-4-aminocyclohexanone intermediate of formula III. The process includes the steps of:
a) cyclizing the compound of Formula III, with a thiourea to obtain tetrahydrobenzothiazole of formula IV.


s Formula IV
b) reacting the compound of Formula IV, with propylating agent in C1-4 alcohols to get of formula V.
HN-
Formula V
H2N,

c) resolving compound of Formula V, with chiral auxiliary to get desired isomer pramipexole
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Cyclization reaction can be carried out in glacial acetic acid. The racemic product can then be resolve by dissolving in suitable aqueous organic solvent in presence of chiral auxiliary like L (+) tartaric acid by the conventional method known in the art. The compound of formula VI, is propylated using different propylating agents known to the skilled artisan. Optionally the propylation is done prior to resolving the racemic product. The propylating agent can be selected from compound of Formula CH3-CH2-CH2-X wherein X is leaving group such as tosylate, mesylate or halide. The reaction can be carried out in presence of aqueous organic solvent such as C1-4 alcohols like methanol, ethanol, propanol or mixture of solvent under reflux condition. The desired compound is obtained by removing solvent under vacuum.
The solvent may be removed by a technique which includes, for example, distillation, distillation under vacuum, evaporation, filtration, filtration under vacuum, decantation and centrifugation.
In yet another aspect, the solution may be cooled before filtration to obtain better yields.
The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Dryer.
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-bromo-4-aminocvclohexanone
To a stirred mixture of 4-aminocydohexanone (1.0 gm) in glacial acetic acid (20ml) was added bromine (1.48 gm) and further diluted with 1 ml of glacial acetic acid. The mixture was stirred at 15°C for 4 hrs. Completion of reaction was
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monitored by TLC. The suspension was mixed with 20 ml of water and ethyl acetate and stirred for 15 minutes. Aqueous layer was separated and concentrated under reduced pressure to get the title compound. Yield: 1.5 gm
Example 2: Preparation of 2.6 -diamino-4.5.6.7- tetrahvdrobenzothiazole
To a stirred mixture of 2-bromo-4-aminocyclohexanone (2.0 gm) in glacial acetic
acid (40 ml) at about 80 °C, was added thiourea. The solution was further heated
for 3 hrs. Completion of reaction was monitored by TLC. The solid product was
precipitated out by cooling the reaction mixture at room temperature.
Yield: 2.3 gm
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WE CLAIM:
1. A 2-bromo-4-aminocyclohexanone compound of Formula III.
Formula III
2. A compound of claim 1, as an intermediate in synthesis of pramipexole or salt
thereof.
3. A process for the preparation of 2-bromo-4-aminocyclohexanone The process
comprising:
a) brominating the compound of Formula II, in glacial acetic acid,

Formula II
extracting 2-bromo-4-aminocyclohexanone of formula III in water immiscible solvent from the reaction mixture

Formula III
4. A process of claim 3, wherein the water immiscible solvent is ethyl acetate.
5. A process for the preparation of pramipexole from the 2-bromo-4-
aminocyclohexanone intermediate of formula III. The process comprising:
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a) cyclizing the compound of Formula III, with a thiourea to obtain
tetrahydrobenzothiazole of formula IV.

-cO-

NH,

Formula IV
b) resolving compound of Formula IV, with chiral auxiliary to get desired isomer of formula V.
„2N^3^""""NH2
Formula V
c) reacting the compound of Formula V, with propylating agent in C1-4 alcohols to get pramipexole
6. A process for the preparation of pramipexole from the 2-bromo-4-aminocyclohexanone intermediate of formula III. The process comprising:
a) cyclizing the compound of Formula III, with a thiourea to obtain tetrahydrobenzothiazole of formula IV.

H2N

^>

NH,

Formula IV
b) reacting the compound of Formula IV, with propylating agent in C1-4 alcohols to get of formula V.
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Formula V
c) resolving compound of Formula V, with chiral auxiliary to get desired isomer pramipexole
7. A process of claim 5 & 6, wherein the cyclization is carried out in presence of glacial acetic acid.
8. A process of claim 5 & 6, wherein the C1-4 alcohols is methanol.
9. A process of claim 5 & 6, wherein resolution of pramipexole is carried out using a chiral auxiliary.
10. A process of claim 9, wherein chiral auxiliary is (L)-(+)-tartaric acid.
Dated this 26th day of February, 2007

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