FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - "A process for the preparation of Ropinirole hydrochloride"
2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention.

Field of the invention:
The present invention relates to an improved process for the preparation of Ropinirole hydrochloride of formula (la).


H,C

Background of the invention:
The chemical name of Ropinirole is 4-[2-(Dipropylamino)ethyl]-ls3-dihydro-2//-indol-2-one, formula C16H24N20 and molecular weight is 260.37. Ropinirole is marketed in the form of its hydrochloride salt. The current pharmaceutical product containing this drug is being sold by Glaxosmithkline using the tradename Requip®, in the form of tablets. The structural formula of Ropinirole is represented by formula (I)

Ropinirole is useful in the treatment of Parkinson's disease. Ropinirole is a dopamine agonist and having selective affinity for dopamine D2-like receptors and little or no affinity for non-dopaminergic brain receptors. Ropinirole is indicated as adjunct therapy to levodopa in patients with advanced Parkinson's disease. Also, recent clinical trials have focused on its use, as monotherapy in patients with early Parkinson's disease.
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Ropinirole was first reported in US patent no. 4,452,808. It discloses the process for the preparation of Ropinirole hydrochloride as shown in following Scheme.

In this process, the final step of cyclization is done by hydrogenation of 2-nitro-6-(2-dirn-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII) in the presence of 5% palladium on carbon in ethanol at 50 p.s.i. over 5.5 hours to give Ropinirole hydrochloride. The yield obtained is 77.5%. However, the use of ethanol at an industrial scale is expensive.
J. Med. Chem. 1985, 28, 1533-1536 and J. Med. Chem. 1986, 29, 939-94 7 also disclose similar process for the preparation of Ropinirole hydrochloride by hydrogenation of 2-nitxo-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII) in the presence of palladium on carbon in ethanol.
US patent no.4,950,765 discloses a process for preparation of Ropinirole or its pharmaceutically acceptable salt. In this- process 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII) is hydrogenated in the presence of sodium hydroxide, water, catalyst and in the presence of a hydrogen donor selected from
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hydrazine hydrate or sodium hypophosphite. The catalyst used is raney nickel, Pt/C or
Pd/C.
Here, the disadvantage of this process is that initially 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride salt is converted to its free base. Subsequently, after the completion of hydrogenation, the free base of Ropinirole has to be converted into its hydrochloride salt to give Ropinirole hydrochloride. This increases the number of steps in the process. The hydrogenation under highly basic condition is more likely to generate impurity compared to hydrogenation of salt.
Moreover, sodium hypophosphite is harmful if swallowed or inhaled and cause irritation to skin, eyes, and respiratory tract. It also cause gastrointestinal disturbance such as nausea, vomiting and diarrhea. It produces toxic flammable phosphine gas on degradation. Hydrazine hydrate is toxic, and may be fatal, if inhaled, swallowed or absorbed through the skin. It is expected to be a human carcinogen and it may cause ONS, eye, liver, kidney and lung damage. It is highly corrosive and is very irritating to respiratory tract, even at low concentrations.
The present inventors have also filed PCT application no. PCT/IN06/00052 which discloses a process of preparation of Ropinirole hydrochloride by using novel intermediates. In this application the cyclization step is done by hydrogenation of 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII) in the presence of palladium on carbon in methanol.
In summary, prior art relating to the process for the preparation of Ropinirole hydrochloride suffers with several drawbacks such as use of very toxic and hazardous reagent and use of expensive solvents.
It is therefore a need to develop an improved process for the preparation of Ropinirole hydrochloride which not only overcomes the aforementioned problems but also provide a
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process which is safe, cost effective, environmental friendly without using any organic solvent or toxic compounds and feasible at commercial production.
The present inventors have directed their research work towards developing an improved process for the preparation of Ropinirole hydrochloride. Surprisingly, the present inventors found that the cyclization of 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII) by doing hydrogenation can be achieved in the presence of Pd/C using water as a solvent. This process eliminates the use of hazardous hydrogenating reagents as well as costly solvents.
This process reduces the number of steps for the preparation of Ropinirole hydrochloride. Further, the reaction takes place in an acidic medium; therefore the chances of formation of impurities are minimal. This process also avoids the use of sodium hydroxide as 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride is not required to be reacted in its free base. Because of these advantages, the process becomes not only economical but also easily applicable at an industrial scale.
Object of the invention:
A primary object of the present invention is to provide an improved process for preparation of Ropinirole hydrochloride of formula (la).
Another object of the present invention is to provide an improved process for preparation of Ropinirole hydrochloride comprising hydrogenation of 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII) in the presence of Pd/C and using water as a solvent, followed by cyclization of compound of formula (Vila) which is generated insitu.
Another object of the present invention is to provide an improved and safe process for the preparation of Ropinirole hydrochloride which avoids the use of hazardous reducing reagents and flammable solvents.
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A further object of the present invention is to provide an improved process for the preparation of Ropinirole hydrochloride which is simple, easy to handle and feasible at commercial scale.
Yet another object of the present invention is to provide an improved process for the preparation of Ropinirole hydrochloride having purity of 99.5% or greater without using any hazardous reagents.
Summary of the invention:
Accordingly, present invention provides an improved process for the preparation of Ropinirole hydrochloride of formula (la)

comprising hydrogenation of 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid

hydrochloride of formula (VII) in the presence of Pd/C and using water as a solvent,

followed by cyclization of compound of formula (Vila) which is generated insitu.

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Detailed description of the invention:
According to the present invention, there is provided an improved process for preparation of Ropinirole hydrochloride comprising hydrogenation of 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII), in the presence of Pd/C and using water as a solvent,

followed by cyclization of compound of formula (Vila) which is generated insitu.


H,C

(Vila)
Catalytic hydrogenation is effected at moderate hydrogen pressure generally ranging from about 3 Kg to about 25 Kg; preferably at 10 to 15 Kg hydrogen pressure. The reaction is generally carried out at an ambient temperature. The reaction can be carried out optionally at elevated temperature in the range of 40°C to 55°C. After completion of the reaction, the mass was filtered. Water immiscible organic solvent is added to the filtrate and basified by adding base. The organic layer is separated and concentrated under reduced pressure.
The example of water immiscible organic solvent as mentioned hereinabove includes but not limited to ester, ether, chlorinated hydrocarbons, aromatic hydrocarbons such as ethylacetate, dichloromethane, toluene, diethylether, diisopropylether, hexane and the like or mixture thereof.
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The example of base as mentioned hereinabove comprise alkali and alkaline earth metal carbonate, bicarbonate and hydroxide, amines and the like or mixture thereof. The example of base as mentioned hereinabove includes but not limited to NaHC03, KHCO3, LiHC03, Na2C03, K2C03, Li2C03, CaC03, MgC03, NaOH, KOH, LiOH, triethylarnine, diethylamine and the like or mixture thereof.
An organic solvent is added to the concentrated mass. The example of an organic solvent includes but not limited to water immiscible organic solvent mentioned hereinabove as well as water miscible solvents such as alcohol or ketones. For example, methanol, ethanol, isopropyl alcohol, acetone and the like.
The ethanolic HCI is added to the above solution to give Ropinirole hydrochloride as product.
The advantage of this process is that it reduces the workup steps as the hydrochloride salt formation is carried out insitu without isolation of Ropinirole base. Moreover, the use of water is industrially cheap. The yield and purity is high compared to prior art processes. The process is eco-friendly with use of no hazardous chemicals.
2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII) can be prepared according to the process mentioned in the US patent no. 4,452,808 or any method known in the art.
The process of preparation of 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII) is elaborated in the following reference example.
Reference Example
Preparation of 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid
hydrochloride
A mixture of 22.0 g (0.105 mole) of 2-methyl-3-nitrophenylacetic acid (V. Askam et al, J. Chem. Soc. (C) 1969 1935) and 25 cc of thionyl chloride was slowly heated to 75° and
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the copious evolution of gasses allowed to moderate. The temperature was raised and the solution was refluxed for 1 hour. The reaction was concentrated in vaccuoa. The residual straw-colored syrup was chased several times with dry toluene, diluted with 100 cc of dry toluene and added to a cool (10°) mixture of 13 g of sodium carbonate in 150 cc of water and 150 cc of toluene containing 14.5 cc (10.6 g, 0.12 mole) of di-n-polyamine with very slow stirring. After 30 minutes, the ice-bath was removed. Stirring was continued for one hour. An additional 0.5 g of solid sodium carbonate was added to the reaction. After 15 minutes, the organic phase was. separated, washed with 5% aqueous sodium carbonate followed by 2N hydrochloric acid and, finally water. The organic solution was dried over magnesium sulfate, concentrated in vacuo and pumped free of solvent to give 29.5 g of 2-methyl-3-nitrophenyl-N,N-di-n-propyl acetamide as a straw-colored syrup.
The total syrup (105 mmoles) was taken up in 250 cc of anhydrous tetrahydrofuran and treated with 160 cc of 1.0 M borane in tetrahydrofuran at room temperature for 1 hour. The reaction was refluxed for 2 hours, then cooled. Excess reagent was destroyed by the cautious addition of dry methanol. This solution was concentrated in vacuo. The residual syrup was treated with 40 cc of 6N hydrochloric acid for 1 hour on the steam-bath, cooled, basified with 40% sodium hydroxide and extracted with 3 portions of ether. The combined organic phase was washed once with brine, concentrated in vacuo and distilled in a Kugelrohr apparatus at 115°-118°/0.1 mm Hg to give 21.6 g of a mobile yellow oil; 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine.
To a solution of 2.38 g (0.103 gram atoms) of sodium metal in 52 cc of absolute ethanol at room temperature was added 18.51 g (0.07 mole) of the nitro compound in one portion, with stirring, followed by 15.42 g (0.103 mole) of diethyl oxalate. The reaction was refluxed under nitrogen for about 20 minutes, cooled, quenched on 700 cc of ice-water and acidified with 3N hydrochloric acid. This aqueous solution was washed with a small volume of ether, basified to pH 8.5 with solid sodium carbonate and extracted with 3 portions of ether. The combined ether extract was washed with saturated brine, dried over anhydrous magnesium sulfate, clarified with charcoal and concentrated in vacuo. The residue was triturated with cold petroleum ether, filtered and air-dried to give 6.0 g of
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ethyl 6-(2-di-n-propylaminoethyl)-2-nitrophenylpyruvate as a yellow powder. The triturate was concentrated in vacuo and distilled to give 7.3 g of recovered starting material which was recycled. In the same manner, a total of three recycles provided 1 l.Og of ethyl-6-(2-di-n-propylaminoethyl)-2-nitrophenylpyruvate.
A cold (10°) solution of 10.24 g (28.1 mmoles) of the pyruvate in 196 cc of 2% sodium hydroxide was treated with 5.0 cc of 30% hydrogen peroxide dropwise over several minutes. The cooling bath was removed and stirring was continued for 1.5 hours during which time the reaction became much lighter in color. A small amount of insoluble material was removed by filtration. The pH was adjusted to 1.5 by the cautious addition (foaming) of about 12 cc of cone, hydrochloric acid. This solution was concentrated in vacuo at 45°, reconstituted with water and evaporated twice more. The residue was slurried in a minimum volume of dilute hydrochloric acid, filtered and air-dried to give 6.40 g of 2-nitro-6(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride as a white powder.
The following example illustrates the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.
Example-1
Preparation of Ropinirole hydrochloride
A mixture of {2-[2-(dipropylamino)ethyl]-6-nitrophenyl}acetic acid hydrochloride (30.0g), 10% Pd/C (6.0 g) and of D.M.Water (600 ml) was added to hydrogenator and hydrogenated at 10 to 12 Kg hydrogen pressure at ambient temperature for 20 to 24 hrs. After completion of the cyclization, the mass was filtered. Ethyl acetate was (210ml) added to the filtrate and basified with 5% Sodium Carbonate solution. Ethyl acetate layer was separated. The aqueous layer was extracted with Ethyl acetate. The combine Ethyl acetate layer was evaporated to dryness under reduced pressure. Fresh Ethyl acetate was added to the residue and the mass was cooled. Ethnolic HC1 was added to the cooled
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mass to get precipitates of hydrochloride salt. The solid is filtered to give Ropinirole hydrochloride (20.7g) (Yield: 81%) HPLC purity: 99.8%
Dated this 23rd day of March 2006
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