FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents
Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A SINGLE STEP PROCESS FOR PREPARATION OF 2,6-DIAMINO-4,5,6,7-
TETRAHYDROBENZATHIAZOLE
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 single step process for preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazolea.
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 single step process for preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole intermediate useful in preparation of pramipexole and 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 medicinal 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.
U.S. patent application 2006/0100256 provides a process for the preparation of 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole from 4-acetamido-cyclohexanone, which is a useful intermediate for making pramipexole.
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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 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 single step cost-effective process for the preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole intermediate useful in preparation of pramipexole and salt thereof. The process involves converting N-(4-hydroxycyclohexyl)acetamide to 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole which avoids the multiple isolation steps.
The term "compound of Formula I or 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 acid addition or salt thereof.
In the aspect of the present invention there is provided a single step process for the preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole intermediate useful in the preparation of pramipexole and salt thereof. The process includes step of:
a) reacting 4-frans-aminocyclohexanol with acetylating agent to produce N-(4-hydroxycyclohexyl) acetamide
b) adding oxidizing agent to produce N-(4-oxocyclohexyl) acetamide
c) adding bromine to produce 2-bromo-N-(4-oxocyclohexyl) acetamide
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d) adding thiourea to produce 6-acetylamino-2-amino-4,5,6,7-tetrahydro-benzthiazole
e) adding an aqueous solution of hydrobromic acid to produce 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole
f) isolating 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole from the reaction mass thereof.
The process of present invention involves reacting 4-f/-a/is-aminocyclohexanol with acetylating agent such as acetic anhydride, acetyl chloride and the like to produce N-(4-hydroxycyclohexyl) acetamide in an organic solvent. The organic solvent includes such as dimethylformamide, dimethylsulfoxide, acetonitrile and the like. The N-(4-hydroxycyclohexyl) acetamide in the reaction mixture is then treated with oxidizing agent at a temperature of 10°-15°C to produce N-(4-oxocyclohexyl) acetamide. The oxidizing agents includes such as Jones reagent, sodium hypochlorite, manganese dioxide, pyridinium dichromate or potassium permanganate.
N-(4-oxocyclohexyl) acetamide solution is then combined with bromine at a temperature in the range of 15°C to 40°C. The bromine is added drop wise to the N-(4-oxocyclohexyl) acetamide solution. After the bromine and the 4-acetamido-N-(4-oxocyclohexyl) acetamide solution have been combined, the mixture is heated to a temperature in the range of 40°C to 50°C until the bromination is complete.
The resultant product i.e. 2-bromo-N-(4-oxocyclohexyl) acetamide in reaction mixture treated with thiourea preferably at a temperature in the range of 80°C to 85°C to produce 6-acetylamino-2-amino-4,5,6,7-tetrahydro-benzthiazole. To this, added aqueous hydrobromic acid and heated to reflux. The reaction mixture is then cooled to 5°C to 15°C and 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole was
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isolated from the reaction mass thereof. The conversion of 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole to pramipexole or salt thereof is well known in the prior art.
It is an important feature of the present invention that the entire synthesis can be carried out in a single step without isolating the jntermediate compounds. Preferably at least four successive steps of steps (a) to (d) are carried out in a single step.
The synthesis of the present invention avoids the need to isolate intermediate compounds, and thus the yield is higher and the processing time is lower. Furthermore, owing to the absence of a solvent such as acetic acid, the reaction conditions are milder which have a positive impact on product purity.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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
Preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole
4-frans-aminocyclohexanol (50.0 gm) was taken in dimethylformamide (500 ml) and cooled to 10°-15°C. To this acetic anhydride (44.34 gm) was added. After completion of reaction, the reaction mixture was concentrated. To the residue obtained thereof acetone (630 ml) was added and cooled to 10°-15°C. To the reaction mixture Jone's reagent was added at 10°-15°C. The mixture was stirred for three hours. The reaction mixture was quenched by adding isopropyl alcohol (252 ml) and concentrated. To the residue, ethyl acetate (630 ml) added and
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stirred for 15-20 minutes. The organic layer was separated and washed with ethyl acetate (630 ml) 2-3 times. Combined the organic layer and concentrated. To the residue added water (250 ml) at the room temperature followed by bromine (56 gm) drop wise in 45-60 minutes at room temperature. The temperature was raised to 45°C and stirred till the reaction is complete. To this reaction mixture thiourea (62.5gm) was added and heated to 80°-85°C for 4-5 hours. To this reaction mass aqueous hydrobromic acid (50 ml) was added and further the reaction mixture was refluxed for 6-8 hours. The reaction mass was then cooled to 10-15°C and basified with addition of sodium hydroxide. The resultant solid was isolated from the reaction mass thereof. Yield: 24-25 gm.
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WE CLAIM:
1. A single step process for the preparation of 2,6-diamino-4,5,6,7-
tetrahydrobenzathiazole intermediate useful in the preparation of pramipexole
and salt thereof. The process comprising
a) reacting 4-frans-aminocyclohexanol with acetylating agent to produce N-(4-hydroxycyclohexyl) acetamide
b) adding oxidizing agent to produce N-(4-oxocyclohexyl) acetamide
c) adding bromine to produce 2-bromo-N-(4-oxocyclohexyl) acetamide
d) adding thiourea to produce 6-acetylamino-2-amino-4,5,6,7-tetrahydro-benzthiazole
e) adding an aqueous solution of hydrobromic acid to produce 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole
f) isolating 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole from the reaction mass thereof.
2. A process of claim 1, wherein the reaction of 4-frans-aminocyclohexanol with
acetylating agent is carried out in presence of organic solvent
3. A process of claim 2, wherein the organic solvent includes such as
dimethylformamide, dimethylsulfoxide, acetonitrile and the like.
4. A process of claim 1, wherein the acetylating agent includes such as acetic anhydride, acetyl chloride and the like.
5. A process of claim 1, wherein the oxidizing agents includes such as Jones reagent, sodium hypochlorite, manganese dioxide, pyridinium dichromate or potassium permanganate.
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6. A process of claim 1, wherein N-(4-oxocyclohexyl) acetamide and bromine are combined at a temperature of from 15°C to 40°C.
7. A process of claim 1, wherein 2-bromo-N-(4-oxocyclohexyl) acetamide and thiourea are combined at 80°C to 85°C.
8. A process of claim 1, wherein the after addition of aqueous solution of hydrobromic acid, the reaction mixture was heated to reflux for 4-5 hours.
9. A process of claim 1, wherein the 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole was isolated by basifying the reaction mixture.
10.A process of claim 9, wherein the reaction mixture was basified by addition of base such as sodium hydroxide, potassium hydroxide, sodium carbonate and the like.

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Abstract
The present invention provides a single step process for preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole intermediate useful in preparation of pramipexole and salt thereof.
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