FORM 2 THE PATENT ACT 1970 & THE PATENTS RULES, 2003
COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION
A process for the preparation of pramipexole.
2. APPLICANT(S)
(a) NAME: Emcure Pharmaceuticals Ltd
(b) NATIONALITY: an Indian Company
(b) ADDRESS: P-l, IT-BT Park
MIDC Fhase-2, Hinjwadi, Pune - 411057, INDIA
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention relates to an improved process for the preparation and isolation of new intermediates in the preparation of pramipexole by using novel catalysts and reagents. Pramipexole is chemically known as (S0-N6-propyl-4,5,6,7-tetrahydro-l,3-benzothiazole-2,6-diamine and has the following structural Formula (1). The present process provides for the preparation and isolation of new intermediates used in the preparation of pramipexole and its salts, hydrates, solvates or derivatives of high purity and yield. The present invention further provides significant reduction in the process related impurities as the new intermediates are isolated to . higher purity and yield.

Pramipexole dihydrochloride monohydrate (PRM), the pharmaceutical active ingredient, is a fine white powder that is soluble in water and some other organic solvents like methanol. PRM is indicated for the treatment of idiopathic Parkinson's disease and schizophrenia. PRM is a type of a dopamine agonist and works by mimicking the activity of dopamine in the brain. It is also used to treat restless leg syndrome, though exactly how it works in this condition is unclear.

An object of the present invention is to provide a novel route for the preparation of pramipexole by using oxidising agents, which are required in catalytic amounts. Besides, giving the product of high purity and yields. In the oxidation step of the present invention new oxidising catalysts were used that significantly improved the step yield and purity of the step product as well as final product. Synthetic strategy for the preparation of pramipexole intermediates of the present invention is depicted by Scheme 1 below.
The patent application US4886812 discloses processes for the preparation of tetrahydrobenzothiazoles or its derivatives; this application generally describes the different derivatives of the tetrahydrobenzothiazoles and its application as pharmaceutical compositions. It also discloses the a few methods of the preparation of the intermediates required for the preparation of the derivatives and its salts. The API pramipexole is covered by this application in several formulations.
In the prior art, after the above application several patent applications are available that cover the different aspects of the preparation of pramipexole and its salts. Few references like PCT publications WO/2006/012276, WO/2006/003220, WO/2001/041763, WO/2004/041797, WO/2006/097014 and WO/2008/041240 suggest different ways of preparation, separation and formulation of pramipexole and its salts. However, the prior art methods do not involve use of TEMPO (2,2,6,6-tetramethylpiperidine-l-oxyl compound) or IBX (2-iodoxybenzoic acid) in oxidation step in the preparation of pramipexole. It also does not disclose a way of preparation

and isolation of the novel intermediates disclosed in the present invention that is a significant part of this invention.
The foregoing processes suffer from serious disadvantages such as low yields of intermediates and final product, use of large amounts of expensive reagents and solvents, and subsequent expense on the scale-up of such processes, rendering these processes less economic for industrial scale manufacturing. Consequently, it would be a significant contribution to the art to provide an improved process for the preparation of pramipexole, which is scalable, cost effective, and environment friendly.
Process of the present invention provides novel route for the synthesis of pramipexole in good yield and high purity by replacing in the oxidation step using K2Cr2O7/ H2SO4 reagents required in large amounts with the new catalysts like TEMPO and IBX. This invention also provides new intermediate compounds (2) that are not described or characterised in the prior art so far.
A prior art reference has described the bromination of 1,4-cyclohexanedione in the presence of methanol to prepare a corresponding ketal. compound; however, the intermediate formed in the art is structurally different and was difficult to isolate due to the instability of the molecule (US 6770761). The methoxy- intermediate of the present invention is stable at room and elevated temperatures having melting point from 112.1 to 112.7 °C. Another ethoxy- intermediate of the present invention is stable at room and elevated temperatures having melting

point from 117 to 119 °C.
Scheme 1 discloses the method of preparation of pramipexole using teachings of the present invention. In the first step, trans 4-aminocyclohexanol is reacted with phthalic anhydride leading to the formation of the N-protected compound (3). In the second step, said protected compound is oxidized to the compound (4) using a catalytic amount of TEMPO or IBX in alkaline conditions (Example 2). This is the first inventive step of the discloser as the oxidizing catalysts used are required in very small amounts compared with the known routes, besides being simple and economic for large-scale preparation of the compound. In the next step, the compound of formula (4) is treated with bromine in the present of alcohol like methanol or ethanol or suitable secondary or tertiary alcohols to obtain the stable compound of formula (2), wherein, R, R' are akyl, secondary or tertiary-alkyl groups. In this step, other alcohols may be used to get the required derivates as can be anticipated from the discloser. After bromination of the compound of formula (2), it is subjected to thiourea treatment in an acidic medium leading the formation of the protected compound of formula (5). Upon deprotecting compound (5), the racemic compound (6) is obtained in higher purity and yield. In the further multiple steps as depicted in Scheme 1 the compound (6) is resolve to compound (7) using L(+)-tartaric acid as known the prior art. After further combination with n-propionaldehyde, the pramipexole base (1) is obtained. From the base, the salts of pramipexole (8) may be obtained as described (Example 8).

Another inventive step of this invention is the isolation of new compounds of formula (2), which have not been reported and characterised before in the prior art.
The novel and useful steps of the invention as shown in Scheme 1 are 1) oxidation of compound (3) to compound (4) using the new oxidising agent TEMPO or IBX in catalytic amounts, and 2) isolation of compounds of formula (2) in higher purity and yield, which is further used in the preparation of pramipexole salts.
In an embodiment of the present invention there is provided an improved route for the preparation and isolation of intermediate compounds of formula (2) of high purity and yield. This step reduces the impurities in the final drug products as well as is economically desirable and easy to scale up for large volume production of the final products.
i.
The process of the present invention is simple, improved, cost-effective, commercially viable, robust and reproducible on an industrial scale. Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art may appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary

skill in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety.
The invention detailed above is illustrated with the following examples for the purpose showing the utility of the invention. Examples below do not restrict the invention in any way from broader application of the reaction chemistry to prepare other derivative molecules from the compound of formula (2). The teaching of this invention can also be used in the preparation of the organic molecules having benzothiazole-2,6-diamine core structures synthesized using the intermediates of the invention disclosed.
List of abbreviations:
DMF = dimethylformamide
HPLC = high performance liquid chromatography
IBX = 2-iodoxybenzoic acid
IPA = isopropyl alcohol
MDC = methylene dichloride
PTSA = p-toulenesulphonamide
TEA = triethylamine
TEMPO = 2,2,6,6-tetramethylpiperidine-l-oxyl compound
Example 1: Preparation of 4-(phthalimido)-cyclohexanol (3)
Take a mixture of 100 gm 4-aminocyclohexanol and 107 gm of triethylamine in 500 mL of DMF plus 500 mL of toluene in a round bottom flask attached to a reflux assembly, heat it to 25 to 35 °C and stir for 30

min. Then charge it with 6.3 gm of PTSA followed by addition of 107 gm of phthalic anhydride. Allow the reaction to proceed at 135 to 145 °C for about 24 h till the product is formed. Check the formation of product by TLC till completion of the reaction. Remove the solvent under vacuum and cool the residue to about 30 °C. Then extract the product with MDC and finally washed with water at room temperature. Then further wash the residue with multiple washes of IPA and vacuum dry to isolate the product at high purity. This process affords about 120 gm (yield of 75 %) of pure compound (3) with purity of 98 % by HPLC.
Example 2: Preparation of 4-(phthalimido)-cyclohexanone (4)
In a 4-neck round bottom flask take 100 gm of 4-(phthalimido)-cyclohexanol (3) in 1000 mL of MDC and stir well. To this add 250 mL of water at about 30 °C and stir well. Then charge 103 gm of sodium bicarbonate and 5 gm of potassium bromide at RT and cool the reaction mixture to -10 to 0 °C and following by addition of 0.16 gm of TEMPO or IBX the low temperature. Then in the reaction add 500 mL of about 10% solution of sodium hypochloride over a period of 60 min. The exothermic reaction increases the temperature up to 5 °C. Then allow the reaction to proceed at 25 to 35 °C for about 2 h till the product is formed. Check the formation of product by HPLC till completion of the reaction. Then extract the formed product in the MDC layer and further wash with sodium thiosulphate solution (25 gm in 500 mL of water) in the biphasic system at 30 °C. Separate the layers and remove organic solvent by distillation at about 45 °C. Then strip the residue with cyclohexane at about 60 °C and

then again wash with cyclohexane under stirring for 4 h at 30 °C. Then filter the residue and completely dry under vacuum at 60 °C for about 7 h. This process affords about 96 gm (yield of 97 %) of pure compound (4) with purity of 98 % by HPLC. The melting point of this compound is from 142.4 to 145.4 °C.
Example 3: Bromination of 4-(phthalimido)-cyclohexanone (4) to compound (2)
Take in a 4-neck round bottom flask 100 gm of compound (4) in 500 mL of methanol and stir well. To this add the bromine solution (72 gm of bromine in 100 mL of methanol) at RT. Then heat reaction mass at 45 °C under stir for 3-4 h. Check the formation of product (compound (2): 2-(3-bromo-4,4-dimethoxycyclohexyl)isoindoline-l,3-dione) by HPLC till completion of the reaction. Then filter the formed solid product, isolate and wash with methanol. Then filter the residue and completely dry it under vacuum at 60 °C for about 8 h. This process affords about 130 gm (yield of 89 %) of pure compound (2) with purity of more than 98 % by HPLC. The melting point of this compound is from 112.1 to 112.7 °C.
Example 3-1: Bromination of 4-(phthalimido)-cyclohexar»one (4) to compound (2-1)
Take in a 4-neck round bottom flask 100 gm of compound (4) in 500 mL of methanol and stir well. To this add the bromine solution (72 gm of bromine in 100 mL of ethanol) at RT. Then heat reaction mass at 45 °C

under stir for 3-4 h. Check the formation of product (compound (2-1): 2-(3-bromo-4/4-diethoxycyclohexyl)isoindoline-l,3-dione) by HPLC till completion of the reaction. Then filter the formed solid product, isolate and wash with methanol. Then filter the residue and completely dry it under vacuum at 60 °C for about 8 h. This process affords about 122 gm (yield of 83 %) of pure compound (2-1) with purity of more than 98 % by HPLC. The melting point of this compound is from 117 to 119 °C.
Example 4: Preparation of 2,6-diamino-4,5,6,7-tetrahydro-l,3-benzothiazole (6)
In a 4-neck round bottom flask take 100 gm of compound (2) in 1000 mL of DM water at 30 "C and stir well. To this slowly add 100 mL of conc. HC1 solution and stir for about 60 min. Then charge 52 gm of thiourea and heat the reaction mass at 75 °C for 24 h. check the formation of product (compound (5)) by HPLC till completion of the reaction. The cool the reaction mass to RT and stir for about 5 h. Filter the formed solid product, isolate and wash with water and then with cyclohexane. Then again filter the residue and completely dry under vacuum at 70 °C for about 8 h. This process affords about 85 gm (yield of 85 %) of pure compound (5) with purity of more than 98 % by HPLC. In the next step, deprotect the 6-amino group of the compound (5) to give 2,6-diamino-4,5,6,7-tetrahydro-l,3-benzothiazole (6) of high purity and yield using methods as known in the prior art.

Example 5: Preparation of