Field of the Invention:
The present invention relates to an improved process for the preparation of pramipexole and its pharmaceutically acceptable salts, particularly pramipexole dihydrochloride. Pramipexole dihydrochloride monohydrate is chemically known in as 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate, which is represented by the following structural formula

Pramipexole dihydrochlride monohydrate is indicated for the treatment of signs and symptoms of idiopathic Parkinson's disease and is commercially available under the brand name of Mirapex®
Background of the Invention:
Pramipexole and its pharmaceutically acceptable salts are disclosed in US 4886812. The patent also described the synthesis of pramipexole dihydrochloride, which involves the reaction of bromine with 4-acetylamido-cyclohexanone in glacial acetic acid, followed by the addition of thiourea under reflux conditions to provide 6-acetylamino-2-amino-4,5,6,7-tetrahydro-benzthiazole-hydrobromide. Thus obtained compound dissolved in hydrobromic acid at reflux temperature to provide the pramipexole dihydrobromide which is then converted into pramipexole dihydrochloride. ■ The said process does not provide the process for the resolution of pramipexole or its intermediate to get the desired isomer.
J.Med, chem. 1987, 30, 494-498 also disclosed a process for the resolution of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole using L(+)-tartaric acid in water medium. The resolved (S)- 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole is treated with triethylamine, propionic anhydride in THF to provide (+)-2-amino-6-priopionamidotetrahydrobenzothiazole, which is then reduced with borane-tetrahydrofuran complex followed by treating with aqueous hydrochloric acid to provide the desired isomer of pramipexole dihydrochloride monohydrate.

The purity of the intermediates as well as the final products obtained as per the prior art processes are not satisfactory and are contaminated with impurities. Hence there is a need in the prior art for an improved process for the preparation of pramipexole and its intermediate with high purity.
The present invention provides an improved process for the preparation of pramipexole dihydrochloride with high yield and purity.
Brief Description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-5, an intermediate in the preparation of pramipexole dihydrochloride. The process comprises of the following steps,
a) Reacting the N-(4-oxocyclohexyl)acetamide compound of formula-2 with bromine in presence of a suitable solvent followed by treating with thiourea to provide the N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yI)acetamide hydrobromide compound of formula-3, then hydrolyzing the compound of formula-3 with a suitable acid in a suitable solvent to provide the 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-4,
b) resolving the 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-4 with suitable resolving agent in a suitable solvent followed by purification and subsequent treatment with a base to provide high pure (S)-4,5,6,7-tetra hydrobenzo[d]thiazole-2,6-diamine compound of formula-5.
The second aspect of the present invention is to provide an improved process for the preparation of pramipexole dihydrochloride monohydrate compound of fomula-la, which comprises of the following steps,
a) Reacting the (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-5 with propionic anhydride in a suitable solvent in presence of a suitable base, followed by purification by acid-base treatment to provide the N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl) propionamide compound of formula-6,

b) reducing the compound of-formula-6 with a suitable reducing agent in a suitable solvent, followed by purification by treating it with an suitable acid and subsequent treatment with a suitable base to provide high pure pramipexole compound of formula-1,
c) treating the pure compound of formula-1 with hydrochloric acid in a suitable solvent, followed by purification from a suitable solvent to provide the pramipexole dihydrochloride monohydrate compound of formula-la.
The third and fourth aspect of the present invention is to provide an improved process for the purification of compound of formula-6 and compound of formula-1 by acid/base or base/acid treatment.
Brief description of the Drawings:
Figure-1: Illustrates the powder X-ray diffraction pattern of pramipexole dihydrochloride
monohydrate.
Figure-2: Illustrates the IR spectrum of pramipexole dihydrochloride monohydrate
Figure-3: Illustrates the DSC thermogram of pramipexole dihydrochloride monohydrate
Detailed Description of the Invention:
The present invention relates to an improved process for the preparation of pramipexole dihydrochloride monohydrate-la.
The first aspect of the present invention is to provide an improved process for the preparation of (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-5,
Formula-5 an intermediate useful for the preparation of pramipexole and its pharmaceutically acceptable salts. The process comprises of the following steps, a) reacting the N-(4-oxocyclohexyl)acetamide compound of formula-2

H.COCHN

^0
Formula-2 with bromine in presence of a suitable solvent like acetic acid followed by treatment with thiourea to provide the N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)acetamide hydrobromide compound of formula-3,
H3COCHN N.,^X'\^ S
NH2 HBr
U-}-
Formula-3 subsequently hydrolyzing the compound of formula-3 with a suitable acid like sulphuric acid in a suitable solvent like water to provide the 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-4,
Formula-4 b) resolving the 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-4 with suitable resolving agent like L(+)-tartaric acid in a suitable polar solvent like water to provide the tartrate salt of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine, and subsequently recrystallizing it from water followed by treating the obtained tartrate salt of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine with an suitable acid in a suitable solvent like water and then treating it with suitable base or aqueous base to provide the pure (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-5.


NH
2

Formula-5
The second aspect of the present invention provides an improved process for the preparation of pramipexole dihydrochloride monohydrate compound of fomula-la,

NH, .2HC1
Formula-la which comprises of the following steps,
a) reacting the (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-5

Formula-5 with propionic anhydride in a suitable alcoholic solvent like methanol, ethanol and isopropanol, n-propanol and water or mixtures thereof, in the presence of a suitable base like triethylamine, diisopropyl ethyl amine preferably triethyl amine to provide N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl) propionamide, followed by treatment with a suitable acid, then washing the reaction mixture with suitable solvent like ethyl acetate, isopropyl acetate and subsequently treating it with a suitable base in a suitable solvent like water to provide the pure N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl) propionamide compound of formula-6,
Formula-6
b) reducing the compound of formula-6 with a suitable reducing agent such as boron
trifluoride etherate or BF3-THF and sodium borohydride complex in a suitable
solvent like tetrahydrofuran, and treating with a suitable acid, followed by treatment
with a suitable base provides pramipexole compound of formula-1,
H3C'
L 1
Formula-1
c) treating the compound of formula-1 with hydrochloric acid in a suitable alcoholic
solvent like methanol, ethanol, isopropanol and water or mixtures thereof followed by

recrystallisation from suitable alcohol solvent like methanol, isopropanol, butanol preferably isopropyl alcohol provides the pure pramipexole dihydrochloride monohydrate compound of formula-la.
The third aspect of the present invention provides a process for the purification of pramipexole compound of formula-1, which comprises of the following steps,
a) Suspending pramipexole in a suitable alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, butanol or aqueous alcohols or water or mixtures thereof,
b) acidifying the above suspension using suitable acid to form a solution,
c) optionally treating with carbon,
d) optionally washing the reaction mixture with a suitable solvents selected ester solvents like ethyl acetate, isopropyl acetate; chloro solvents like methylenechloride, chloroform and hydrocarbon solvents like toluene, heptane, hexane and cyclohexane,
e) stirring the said solution;
f) basifying the above solution to crystallize the product,
g) filtering the solid, washing it with suitable solvent to provide the pure compound of formula-1.
The fourth aspect of the present invention provides a process for the purification of N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl) propionamide compound of formula-6, which comprises of the following steps,
a) Suspending the compound of formula-6 in suitable solvent like aqueous alcoholic solvents selected from methanol, ethanol, isopropanol, n-propanol, butanol or aqueous alcohols or water or mixtures thereof,
b) acidifying the above suspension using suitable acid to form a solution,
c) washing the reaction mixture with a suitable ester solvent like ethyl acetate, isopropyl acetate; chloro solvents like methylenechloride, chloroform and hydrocarbon solvents like toluene, heptane, hexane and cyclohexane,
d) basifying the above solution with a suitable base to crystallize the product,

e) filtering the solid, washing it with a suitable solvent to provide the pure compound of fomiula-6.
The suitable acid used as per any aspect of the present invention is selected from hydrochloric acid, hydrobromic acid, acetic acid, benzenesulfonic acid, camphoursulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid, methane sulfonic acid, oxalicacid, phosphoric acid and sulfuric acid.
The suitable base used as per any aspect of the present invention is selected from sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, sodium bicarbonate, potassium bicarbonate and ammonia.
The pramipexole or its pharmaceutically acceptable salts can be micronised or milled to get the desired particle size. The pramipexole dihydrochloride monohydrate is prepared as per the prior art process having mean particle size approximately less than 150 microns.
The powder X-ray diffractogram & Infrared spectrum of pramipexole hydrochloride monohydrate prepared as per the process disclosed in Journal of Medicinal Chemistry, 1987, 30, 494-498 is shown in figure-1 & figure-2 respectively. The PXRD and IR spectrum of pramipexole dihydrochloride monohydrate prepared as per the present invention is similar to the PXRD and IR shown in the figure 1 & 2 respectively.
XRD analysis of pramipexole and its pharmaceutically acceptable salts were carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min. FT-IR spectrum of pramipexole and its pharmaceutically acceptable salts were recorded on Thermo model Nicolet-380 as KBr pellet. The thermal analysis of pramipexole and its pharmaceutically acceptable salts were carried out on Waters DSC Q-10 model differential scanning calorimeter.

The related substance of pramipexole and its pharmaceutically acceptable salts were analyzed by HPLC using the following conditions:
Column: Symmetry CI8, 250 X 4.6 mm, 5 jim; Flow rate: 0.8 ml/min; wavelength: 265 nm; Temperature: 45°C; Load: 20 |il; Run time: 55 min; and using buffer (potassium dihydroggen sulphate &. octane-1-sulfonic acid in water) and acetonitrile in 75:25 v/v ratio as a diluent.
The chiral purity of pramipexole and its pharmaceutically acceptable salts as well the intermediate were analyzed by HPLC using the following conditions: Column: Chiralpak lA, 250 X 4.6 rmm 5^m; Flow rate: 1.0 ml/min; wavelength: 265 nm; Temperature: 25°C; Load: 20 \i\; Run time: 20 min; and using a mixture n-hexane;ethanol and DEA as a diluent.
The following are the process related impurities which are generally observed in the synthesis of pramipexole and its pharmaceutically acceptable salts.

Impurity Structure Name
(S)-4,5,6,7-Tetrahydrobenzothiazole-2,6-diamine (herein designated as "IMP-l")
H3CH2CHN/,,^^\^S (S)-2-Amino-4,5,6,7-Tetrahydro-6-(ethylamino)- benzothiazole (herein designated as "IMP-2")
H3CH2COCHN/, ^-^X^^S (S)-2-Amino-4, 5, 6, 7-tetrahydro-6-(propylamido)benzothiazole (herein designated as "IMP-3")
r Jf ^^—NHCH2CH2CH3 (S)-2,6-Di(propylamino)-4,5,6,7-tetrahydro-Benzothiazole (herein designated as "IMP-4")
H3CH2COCHN/,^^^S
r T y—NHCOCH2CH3 (S)-2,6-Di(propylamido)-4,5,6,7-tetrahydro benzothiazole (herein designated as "IMP-5")
/\^N^^^ S 2HCI.H2O R- Pramipexole dihydrochloride monohydrate (herein designated as "IMP-6") (Other isomer)

The present invention is schematically represented as follows:

HBr
H3C0CHN

n
Formula-2

H3COCHN. ^'S. C
Bromine >^ >^ ^^
iniourea *
Formula-3

water

H,N

^NHj
//
"N
Formula-4

L(+)-tartaric acid
Water
KOH

N
H3CH2COCHN/,
Formula-6

NH,

Propionic anhydride
Methanol
Water

Formula-5

NH,

BF3diethyletherate
THF
NaBH4


N
H,C

H

Formula-1

NH,

Methanol HCl
Isopropanol

H,C

H
,N.

Formula-la

NH2 .2HC1 .H,0

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yI)
acetamide hydrobromide compound of formula-3:
Bromine (41.35 ml) was added to a solution of N-(4-oxocyclohexyl)acetamide (100 grams) in acetic acid (500 ml) at 25-35°C, stirred for 45 minutes and thiourea (50 grams) was added to it. The reaction mixture was heated to reflux and stirred at reflux for 3 hours, cooled and stirred for 2 hours at 25-35°C. The obtained solid was filtered, washed with acetone and dried to get the title compound. Yield: 200 grams
Example-2: Preparation of 4,5,6,7-tetrahydrobenzo[d]thiazoIe-2,6-diamine compound of formula-4:
Aqueous sulphuric acid (67 grams of sulphuric acid in 200 ml of water) was added to N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)acetamide hydrobromide compound of formula-3 (200 grams) taken in water (200 ml). The reaction mixture was heated to reflux and stirred for 10 hours. The reaction mixture was cooled to 0-5°C, basified with aqueous sodium hydroxide solution and stirred for 90 minutes at 25-30°C. The solid formed was filtered, washed with water and dried to get the title compoimd. Yield: 80 grams Purity by HPLC: 98.47 %
Example-3: Preparation of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-4:
Bromine (41.35 ml) was added to a solution of N-(4-oxocyclohexyl)acetamide (100 grams) in acetic acid (500 ml) at 25-35°C, stirred for 45 minutes and thiourea (50 grams) was added to it. The reaction mixture was heated to reflux and stirred at reflux for 3 hours, cooled and stirred for 2 hours at 25-35°C. The obtained N-(2-amino-4,5,6,7-

tetrahydrobenzo[d]thiazol-6-yl)acetamide hydrobromide compound of formula-3 was filtered, washed with acetone. Water (200 ml) and aqueous sulphuric acid (67 grams of sulphuric acid in 200 ml) was added to the above obtained wet solid. The reaction mixture was heated to reflux and stirred for 10 hours. The reaction mixture was cooled to 0-5°C, basified with aqueous sodium hydroxide solution and stirred for 90 minutes at 25-30°C. The solid formed was filtered, washed with water and dried to get the title compound. Yield: 90 grams Purity by HPLC: 98.46 %
ExainpIe-4: Preparation of (S)-4,5,6,7-tetrahydrobenzo[d]thiazoIe-2,6-diamine compound of formula-S:
L(+)-tartaric acid (88 grams) was added to a solution of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-4 (100 grams) in water (1 L) at 70-75°C. The reaction mixture was stirred at reflux for an hour, slowly cooled to 25-30°C and stirred for 4 hours. The solid formed was filtered and solid washed with water. Water (700 ml) was added to the obtained wet solid. The reaction mixture was heated to reflux and stirred for 45 minutes. The reaction mixture cooled to 25-30°C and stirred for 90 minutes. The solid obtained was filtered, washed with water. The wet solid was dissolved with aqueous hydrochloric acid (40 ml in 100 ml of water) and subjected to carbon treatment. The reaction mixture was filtered through hyfiow and aqueous potassium hydroxide (112 gram in 160 ml of water) was added to it. The reaction mixture was stirred for 90 minutes at 25-30°C. The solid obtained was filtered, washed with water and dried to get the title compound Yield: 40 grams
Chiral Purity by HPLC: 99.45 % & R-isomer: 0.55% Purity by HPLC: 99.80 % & 0.13 % (RT 24.92)
Example-5: Preparation of N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl) propionamide compound of formula-6:
Triethyl amine (74 ml) was added to a mixture of (S)-4,5,6,7-tetra hydrobenzo[d]thiazole-2,6-diamine compound of formula-5 ( 90 grams) in methanol (450

ml) at 25-30°C. Propionic anhydride (69.21 grams) was added to the reaction mixture at 10-20°C and stirred for 90 minutes. The reaction mixture was quenched with water and stirred for 20 minutes at 25-30°C. Methanol was distilled off from the reaction mixture under reduced pressure at 50-55°C to get the title compound.
Example-6: Purification of N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl) propionamide compound of formuIa-6:
Water (450 ml) was added to the crude compound of formula-6 obtained as per the example-5 at 25-30°C. The reaction mixture was acidified with aqueous hydrochloric acid at 0-5°C, stirred and washed with reaction mixture with ethyl acetate to remove the dipropyl ami do impurity at 10-15°C. The reaction mixture expelled with nitrogen and then basified with aqueous potassium carbonate and stirred for an hour at 10-15°C. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 95 grams Purity by HPLC: 99.33%
Example-?: Preparation of Pramipexole compound of formula-1:
Sodiumborohydride (33.2 grams) and borontrifluoride etherate (130 ml) was added to N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl) propionamide compound of formula-6 (65 grams) in tetrahydrofuran (390 ml) at 0-5°C. The reaction mixture temperature was raised initially to 25-30°C then heated to 45-50°C and stirred for 4 hours. The reaction mixture was cooled and then added to ice water at below 10°C, stirred for 10 minutes. Hydrochloric acid (97.5 ml) was added to the reaction mixture and then solvent was distilled off under reduced pressure at 55-60°C. The reaction mixture was cooled to 25-30°C, basified with aqueous sodium hydroxide solution at 5-10°C, stirred for 45 minutes and then stirred for 90 minutes at 25-30°C. The solid formed was filtered and washed with water.
Purity by HPLC: 99.45 %; IMP-3 = 0.21%; IMP-1 = 0.02 %; IMP-2 = 0.04%; Impurity at 1.20 RRT = 0.09%; Impurity at 1.40 RRT = 0.07 %; IMP-4 = 0.10 %. Purification of pramipexole compound of formula-1:
The above wet solid dissolved in a mixture of methanol (325 ml) and hydrochloric acid (97.5 ml), stirred for 30 minutes 25-30°C and subjected to carbon

treatment. Methanol from the filtrate was distilled off completely under reduced pressure at below 55°C. Isopropyl alcohol (65 ml) was added to the residue, distilled off it and then added isopropyl alcohol then stirred for 15 minutes. The reaction mixture was heated to reflux, stirred for 45 minutes then cooled to 10-15°C and stirred for 1.5 hours. The solid formed is filtered and washed with isopropyl alcohol. Wet solid was dissolved in water, basified with sodium hydroxide solution and stirred for 2 hours at 25-30°C. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 47 grams Melting point: 116-120°C
Purity by HPLC: 99.76 %; IMP-3 = Not Detected; IMP-1 = Not Detected ; IMP-2 = 0.04%; Impurity at 1.20 RRT = 0.06%; Impurity at 1.40 RRT = 0.05 %; IMP-4 = 0.04 %.
Example-S: Preparation of pramipexole dihydrochloride monohydrate compound of formula-la:
Hydrochloric acid (75 ml) was added to a solution of pramipexole (50 grams) in methanol (250 ml) at 25-30°C and stirred for 45 minutes. The reaction mixture subjected to carbon treatment, stirred and filtered through hyflow. The solvent from the filtrate was distilled off completely under reduced pressure at below 60°C. Isopropyl alcohol (50 ml) was added to the residue and distilled off it again. Water (13 ml) and isopropyl alcohol (250 ml) was added to the residue, heated the reaction mixture to reflux temperature and stirred for 20 minutes. The reaction mixture was initially cooled to 25-30°C, stirred for 1.5 hour and then cooled to 10-15°C and stirred for 3 hours. The solid formed was filtered, washed with isopropyl alcohol and dried to get the title compound. Yield: 70 grams S.O.R:-67.3°[cl,MeOH]
Purity by HPLC: 99.89 %; IMP-2 = 0.02 %; Impurity at 1.16 RRT = 0.03%; Impurity at 1.45 RRT = 0.03%; IMP-4 = 0.02 % Chiral purity by HPLC: 99.85%; 0.01% (R-isomer)
Particle Size Distribution: D(0.1):8.9|am; D(0.5): 50.858^m; D(0.9): 307.1 [im; D[4,3]: 122.23m

We Claim:
1. An improved process for the preparation of (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-5,

b) resolving the 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formuIa-4 with suitable resolving agent like L(+)-tartaric acid in a suitable polar solvent like water to provide the tartrate salt of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine, and subsequently recrystallizing it from water followed by treating the obtained tartrate salt of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine with an suitable acid in a suitable

solvent like water and then treating it with suitable aqueous base to provide the pure (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-5.
2. An improved process for the preparation of pramipexole dihydrochloride monohydrate compound of fomula-la,

with propionic anhydride in a suitable alcoholic solvent like methanol, ethanol, n-propanol, isopropanol and water or mixtures thereof, in the presence of a suitable base like triethylamine, diisopropyl ethyl amine to provide N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl) propionamide, followed by treatment with a suitable acid, then washing the reaction mixture with suitable solvent like ethyl acetate, isopropyl acetate and subsequently treating with a suitable base in a suitable solvent like water to provide pure N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl) propionamide compound of formula-6,

b) reducing the compound of formula-6 with a suitable reducing agent such as boron trifluoride etherate or BF3-THF & sodium borohydride complex in a suitable solvent like tetrahydrofuran, treating with a suitable acid and subsequently treating with a suitable base provides pramipexole compound of formula-1,


c) treating the compound of formula-1 with hydrochloric acid in a suitable alcoholic solvent like methanol, ethanol, isopropanol and water or mixtures thereof followed by recrystallisation from suitable alcohol solvent like methanol, isopropanol, butanol to provide the pure pramipexole dihydrochloride monohydrate compound of formula-la.
3. An improved process for the preparation of pramipexole dihydrochloride monohydrate compound of formula-la,

with bromine in presence of a suitable solvent like acetic acid followed by treating with thiourea to provide the N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)acetamide hydrobromide compound of formula-3

and subsequently hydrolyzing the compound of formula-3 with a suitable acid like sulphuric acid in a suitable solvent like water to provide the 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-4,

Formula-4 b) resolving the 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-4 with suitable resolving agent like L(+)-tartaric acid in a suitable polar solvent like water to provide the tartrate salt of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine, subsequently recrystallizing it from water followed by treating the obtained tartrate salt of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine with an suitable acid .in a suitable solvent like water, followed by treating h with suitable aqueous base to provide the pure (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-5.

Formula-5
c) reacting the (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of
formula-5 with propionic anhydride in a suitable alcoholic solvent like methanol,
ethanol, isopropanol and water or mixtures thereof, in the presence of a suitable
base like triethylamine, diisopropyl ethyl amine to provide N-((S)-2-amino-
4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl) propionamide, followed by treatment
with a suitable acid, then washing the reaction mixture with suitable solvent like
ethyl acetate, isopropyl acetate and then subsequently treating with a suitable
base in a suitable solvent like water to provide the pure N-((S)-2-amino-4,5,6,7-
tetrahydrobenzo[d]thiazol-6-yl) propionamide compound of formula-6,
Formula-6
d) reduction of compound of formula-6 with a suitable reducing agent such as boron
trifluoride etherate or BF3-THF & sodium borohydride complex in a suitable

solvent like tetrahydrofuran, treating with a suitable acid, and subsequently treating with a suitable base provides pramipexole compound of formula-!,
H3C'
I 1
•N
Formula-1 e) treating the compound of formula-1 with hydrochloric acid in a suitable alcoholic solvent like methanol, ethanol, isopropanol and water or mixtures thereof followed by recrystallisation from suitable alcohol solvent like methanol, isopropanol, n-propanol, butanol to provide the pure pramipexole dihydrochloride monohydrate compound of formula-la.
4. A process for the purification of pramipexole compound of formula-1, which
comprises of the following steps,
a) Suspending pramipexole in a suitable alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, butanol or aqueous alcohols or water or mixtures thereof,
b) acidifying the above suspension using suitable acid to form a clear solution,
c) optionally treating with carbon,
d) optionally washing the aqueous mass with a suitable solvents selected ester solvents like ethyl acetate, isopropyl acetate; chloro solvents like methylenechloride, chloroform and hydrocarbon solvents like toluene, heptane, hexane and cyclohexane,
e) stirring the said solution,
f) basifying the above solution to crystallize the product,
g) filtering the solid, washed with suitable solvent to provide the pure compound of formula-1.
5. A process for the purification of N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-
yl)propionamide compound of formula-6, which comprises of the following steps.

a) Suspending the compound of fonnula-6 in suitable solvent like aqueous alcoholic solvents selected from methanol, ethanol, isopropanol, n-propanol, butanol or aqueous alcohols or water or mixtures thereof,
b) acidifying the above suspension using suitable acid to form a clear solution,
c) washing the aqueous solution with a suitable ester solvent like ethyl acetate, isopropyl acetate; chloro solvents like methylenechloride, chloroform and hydrocarbon solvents like toluene, heptane, hexane and cyclohexane,
d) basifying the above solution with a suitable base to crystallize the product,
e) filtering the solid, washing with a suitable solvent to provide the compound of formula-6.

6. The process according to any of the preceding claims, wherein the acid is selected from hydrochloric acid, hydrobromic acid, acetic acid benzenesulfonic acid, camphoursulfonic acid, ethanesulfonic acid, fumaric acid, maleic acid, methane sulfonic acid, oxalicacid, phosphoric acid and sulfuric acid.
7. The process according to any of the preceding claims, the suitable base is selected from sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodiumbicarbonate, potassium bicarbonate and ammonia.
8. A process for the purification of pramipexole compound of formula-1, which comprises of the following steps,

a) Suspending pramipexole in methanol,
b) acidifying the above suspension using hydrochloric acid to form a clear solution,
c) treating with carbon,
d) optionally washing the filtrate with ethyl acetate,
e) stirring the said solution,
f) basifying the above solution with sodium hydroxide to crystallize the product,
g) filtering the solid, washed with methanol to provide the pure compound of formula-1.

9. A process for the purification of N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-
yl)propionamide compound of formula-6, which comprises of the following steps,
a) Suspending the compound of formula-6 in water,
b) acidifying the above suspension using aqueous hydrochloric acid to form a clear solution,
c) washing the reaction mixture with ethyl acetate,
d) basifying the above solution with a aqueous potassium carbonate to crystallize the product,
e) filtering the solid, washing with water to provide the compound of formula-6.
10. An improved process for the preparation of pramipexole dihydrochloride
monohydrate compound of formula-la,
H3C' ^^ -.^■"^--'S,
I y.., .2HC1
Formula-la
which comprises of the following steps;
a) reacting the N-(4-oxocyclohexyl)acetamide compound of formula-2
H3COCHN,


Formula-2 with bromine in presence acetic acid followed by treatment with thiourea to provide the N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)acetamide hydrobromide compound of formula-3,
H3COCHN \^\^ s
NH2 HBr
UL^
Formula-3 subsequently hydrolyzing the compound of formula-3 with aqueous sulphuric acid to provide the 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-4,

Formula-4 b) resolving the 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-4 with L(+)-tartaric acid in a water to provide the tartrate salt of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine, subsequently recrystallizing it from water followed by treating the obtained tartrate salt of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine with aqueous hydrochloric acid and then treating it with suitable aqueous sodium hydroxide to provide the pure (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of formula-5.

N Formula-5
c) reacting the (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine compound of
formula-5 with propionic anhydride in methanol, in the presence of a suitable
base like triethylamine to provide N-((S)-2-amino-4,5,6,7-tetra
hydrobenzo[d]thiazol-6-yl) propionamide, followed by treatment with
hydrochloric acid in methanol, then washing the reaction mixture with ethyl
acetate subsequently treating with aqueous potassium carbonate to provide the
pure N-((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl) propionamide
compound of formula-6,
Formula-6
d) reducing the compound of formuIa-6 with a suitable reducing agent such as boron
trifluoride etherate & sodium borohydride complex in tetrahydrofuran, treating
with a aqueous hydrochloric acid, and subsequently treating with a aqueous
sodium hydroxide provides pramipexole compovmd of formula-1,


e) treating the compound of formula-1 with hydrochloric acid in methanol, followed by recrystallisation it from aqueous isopropyl alcohol to provide the pure pramipexole dihydrochloride monohydrate compound of formula-la.