FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
'A METHOD OF MAKING 2,6-DIAMINO-4,5,6,7-TETRAHYDRO-
BENZOTHIAZOLE"
CIPLA LIMITED, an Indian company, of 289 Bellasis road, Mumbai Central, Mumbai 400 008, India
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 a method of making 2, 6-diamino-4, 5, 6, 7-tetrahydro-benzothiazole, an intermediate useful in the production of pramipexole. The invention also relates to a synthesis of pramipexole.
Background of the Invention
(S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazolediamine (or (SH-amino-4,5,6.7-
tetrahydro-6-(propylamino)benzothiazole), more commonly known as pramipexole, is used in both early and late Parkinson's disease as a dopamine agonist, to stimulate dopamine receptors m me brain. Tins has been described in EP 01S6 087.
- EP 0 1S6 087 also describes me synthesis of various tetrahydro benzodnazoles. including pramjpexole. m particular, toe synnSesb of piainipex^
pathway is described. An initial reaction between bromine and 4-acetylamido-cycJohexanone is carried oat in glacial acetic acid, with stirring for several hours, at room temperature. This is followed by die addition of thiourea under refluxing conditions. The reaction mixture is cooled, and crystals of 6^acetylamino-2-amino-4.5,6,7-tetrahydro-benzthiazole-hydrobromide arc precipitated. The precipitate is filtered, dien washed with water and acetone. The crystals are then dissolved in hydrobromic acid and the solution is refluxed for several hours. The solution is then concentrated by evaporation and the residue dissolved in methanol, from which crystals of 2,6-diamino-4,5,6,7-teirariydro-benzthia2oIe-dihydrobromide are formed. Subsequently, the 2,6-diaminc^,5,6,7-tetrahydro-benzthia2ole-dihydrobromide may be converted to pramixexole.
This synthesis is illustrated by the following reaction scheme:

We have now found a way of synthesizing 2, 6-diamino-4, 5, 6, 7-tetrahydro-benzothiazole from 4-acetamido-cyclohexanone, which avoids the multiple isolation steps used in the previously described processes.
Statement of the Invention
Accordingly, the present invention relates to a method of making 2, 6-diamino-4,5,6, 7-tetrahydro-benzothiazole, which method comprises the steps in sequence of, (i) reacting bromine with a solution of 4-acetamido-cyclohexanone in water to produce 2-bromo-4-acetamido-cyclohexanone; (ii) adding thiourea to produce 6-acetylamino-2-amino-4, 5, 6, 7-tetrahydro-benzothiazole; (iii) adding an aqueous solution of hydrobromic acid to produce 2, 6-diamino-4,-tetrahydro-benzothiazole; (iv) isolating 2, 6-diamino-4, 5, 6, 7-tetrahydro-benzothiazole; and optionally converting it to pramipexole, wherein the steps (i) to (iv) are carried in a single reaction vessel and brominated intermediate of step (i) is not isolated.
It is an important feature of the present invention that step (iii) is carried out without
any isolation of the 6-acetybBamo-2-amino –4,5,6,7-tetrahydro –benzthiazole produced in step
(ii) Thus die entire synthesis can be earned out in a single reaction vessel Preferably at least three successive steps of steps OD to (iv) are earned out in a single reaction vessel
Prior to step (i)> the method may comprise die step of oxidising 4-acetamido-cydobexanol ID produce 4-ac^ainido-cyclohexanooc. This step may be carried out in the same reaction vessel as subsequent steps (0 to (rv)> thereby avoiding an additional isolation step.
The oxidation reaction may be carried out using oxidising agents including, for example, Jones reagent, sodium hypochlorite, manganese dioxide, pyridinium dichromate or potassium permanganate.
In step (i), the 4-acetamido-cyclohexanone solution and the bromine are preferably combined in the reaction vessel at a temperature in the range S°C to 75°C, morepreferably in me range 15*C to 40°C, and roost preferably about room temperature (approximately 25°C). The bromine is preferably added dropwise to the 4-acetamido-cyclohexanone solution. After the bromine and the 4-acetamido-cyclohexanone solution have been combined, the mixture is preferably heated to a temperature in the range 30°C to 80°C, more preferably 40°C to 50X,

WE CLAIM:
1. A method of making 2, 6-diamino-4, 5, 6, 7-tetrahydro-benzothiazole, which method comprises the steps in sequence of, (i) reacting bromine with a solution of 4-acetamido-cyclohexanone in water to produce 2-bromo-4-acetamido-cyclohexanone; (ii) adding thiourea to produce 6-acetylamino-2-amino-4, 5, 6, 7-tetrahydro-benzothiazole; (iii) adding an aqueous solution of hydrobromic acid to produce 2, 6-diamino-4,-tetrahydro-benzothiazole; (iv) isolating 2, 6-diamino-4, 5, 6, 7-tetrahydro-benzothiazole; and optionally converting it to pramipexole, wherein the steps (i) to (iv) are carried in a single reaction vessel and brominated intermediate of step (i) is not isolated.
2. A method as claimed in claim 1, wherein step (iii) is carried out without isolating the 6- acetylamino-2-amino-4, 5, 6, 7-tetrahydro-benzothiazole produced in step (ii).
3. A method as claimed in claims 1 or 2, wherein any three successive steps of steps (i) to (iv) are carried out in a single reaction vessel.
4. A method as claimed in claims 1, 2 or 3, wherein, prior to step (i), 4-acetamido-cyclohexanol is oxidized to produce 4-acetamido-cyclohexanone.
5. A method as claimed in claims 1 and 4, wherein the step of oxidising 4-acetamido-cyclohexanol and steps (i) to (iv) are carried out in a single reaction vessel.
6. A method as claimed in any preceding claim wherein in step (i) the solution of 4-acetamido-cyclohexanone in water and bromine are combined at a temperature of from 15°C to 40°C.
7. A method as claimed in any preceding claim wherein, after the bromine and the 4- acetamido-cyclohexanone solution have been combined, the mixture is

heated to a temperature of from 40°C to 50°C, and maintained at or near this temperature until the bromination is complete.
8. A method as claimed in any preceding claim wherein, in step (ii), the temperature is increased to 70°C to 90°C.
9. A method as claimed in any preceding claim, wherein step (iii) is carried out under refluxing conditions.
10. A method as claimed in any preceding claim wherein, after step (iii) but before step (iv), the reaction mixture is cooled to 5°C to 20°C, then neutralised.
11. A method as claimed in any preceding claim, wherein the 2, 6-diamino, 6, 7-tetrahydro-benzothiazole isolated in step (iv) is resolved into its R (+) and S (-) enantiomers and the R (+) and/or S (-) enantiomer is recovered.
12. A method as claimed in any preceding claim, wherein 2, 6-diamino-4, 5, 6, 7-tehahydro-benzothiazole is converted to pramipexole by reaction with a propionyl halide.
13. A method as claimed in claim 12, wherein the 2, 6-diamino-4, 5, 6, 7-tetrahydro-benzothiazole comprises the R (+) enantiomer.
14. A method as claimed in claim 12, wherein the 2, 6-diamino-4, 5, 6, 7-tetrahydro-benzothiazole comprises the S (-) enantiomer.
15. A method as claimed in claim 12, wherein the 2,6-diamino-4, 5,6, 7-tetrahydro-benzothiazole comprises a racemic mixture.

16. A method as claimed in claim 12, wherein the pramipexole is resolved into its R (+) and S (-) enantiomers and the R (+) and/or S (-) enantiomer is recovered.
17. A method of making 2, 6-diamino-4, 5, 6, 7-tetrahydro-benzothiazole substantially as herein described with reference to the foregoing examples.