DESCRIPTION

The present invention provides improved process for the preparation of ropinirole hydrochloride. The process relates to the effect of use of anti oxidants on the purity of ropinirole hydrochloride especially the reduced quantity of 3 –oxo ropinirole Hydrochloride as one of the impurities.

Ropinirole hydrochloride of Formula I is chemically known as 4-[2-(dipropylamino) ethyl]-1, 3-dihydro-2H-indol-2-one hydrochloride.

Formula 1

US patent No 4,452,808 discloses the process of preparation of ropinirole hydrochloride starting from 2-methyl-3-nitro phenyl acetic acid in various stages to convert to 6-(2-di-n-propylaminoethyl)-2-nitro phenyl acetic acid hydrochloride. This intermediate is reduced with palladium/carbon to give ropinirole hydrochloride.

Alternative processes for the preparation of ropinirole are described in J.Med.Chem.1985, 28, 1533-1536 and US patent nos. 7,230,118, US 7,378,439 and US 7619095.

The present inventors while developing process for the preparation of ropinirole and its pharmaceutically acceptable salt especially ropinirole hydrochloride have developed an improved process which converts the material 2-nitro-6-2(di-n-propylaminoethyl)-phenyl acetic acid hydrochloride (NDPA HCl) to ropinirole hydrochloride having unreacted NDPA HCl less than 0.01% and have 3-oxo impurity of less than 0.01% in the ropinirole hydrochloride with the use of antioxidants.
In one of the aspect of the invention a process for the preparation of Ropinirole Hydrochloride, the process includes steps of;
a) hydrogenation of NDPA HCl of Formula II in presence of 5% Pd/C in methanol and water at room temperature.

Formula II
b) removal of solvent from the reaction mixture of step a) in presence of anti oxidant.
c) Isolating Ropinirole hydrochloride from the reaction mixture thereof.

The process of conversion of NDPA HCl (Formula II) to crude ropinirole hydrochloride comprises hydrogenation of suspended NDPA HCl in methanol and water in the presence of 5% Palladium/Carbon (Pd/C) catalyst. The hydrogenation may be carried out at 2-12 Kg pressure and at room temperature i.e. 25–350C. After the completion of the hydrogenation the catalyst may be filtered and the filtrate may be concentrated in the presence of antioxidant to obtain residue. The residue may be isolated by suspending in isopropyl alcohol and stirred to obtain the product. The product is isolated washed and dried to ropinirole hydrochloride (Formula I) having purity 99.8% or more when measured by HPLC.

In an embodiment of the process the purification of ropinirole hydrochloride having 3-oxo impurity up to 0.2% or more to ropinirole hydrochloride with 3-oxo impurity 0.02% or less the process includes the step of;
a) contracting Ropinirole hydrochloride having 3-oxo impurity up to 0.15% with water,
b) adjusting pH of solution between 7.5 to 10.5 with suitable base in presence of antioxidants,
c) extracting Ropinirole base in halogenated solvent,
d) isolating pharmaceutically acceptable salt of Ropinirole having 3-oxo impurity 0.02% or less.

The Ropinirole hydrochloride having 3-Oxoimpurity is 0.2% or more may be dissolved in water comprising antioxidants and the pH may be maintained at 7.5 – 10.5 using suitable base solution such as aqueous solution of carbonate, bicarbonate, hydroxide of alkali metal like sodium and potassium. The antioxidants may be either one or more of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), Sodium dithionite, Sodium metabisulphite and citric acid. The ropinirole may be extracted with halogenated solvent like chloroform, dichloromethane, ethylene dichloride and concentrated to obtain ropinirole base as oil. The ropinirole base may be dissolved in acetonitrile and water. Subsequently concentrated hydrochloric acid may be added at 10 - 200C. The crystallized material may be stirred, filtered and dried to obtain ropinirole hydrochloride with HPLC purity 99.94% or higher and 3-oxo impurity less than 0.02%.

The impurities in ropinirole and its pharmaceutically acceptable salt especially ropinirole hydrochloride prepared by the improved process of this invention includes but not limited to one or more of the compounds of Formula III, Formula IV, Formula V and Formula VI.

Formula III
3 –oxo- ropinirole HCl

Formula IV
Monopropyl ropinirole HCl

Formula V
Hydroxy ropinirole HCl

Formula VI
Amine HCl (Uncyclized)

Thus, the invention provides an efficient process for the preparation of ropinirole of Formula I and its pharmaceutically acceptable salts more such as ropinirole hydrochloride, which offers significant commercial advantages when preparing on an industrial scale. The process is simple, environment friendly and economical and leads o enhanced yield.

The present invention is further illustrated by the following examples 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

Part-A: Ropinirole Hydrochloride crude:

NDPA HCl (100 gm) was suspended in methanol (1000 ml) and water (50 ml), and then 5% Pd/C (12.5 gm, 50 % wet) was added. The contents were subjected to hydrogenation at 10-12 Kgs pressure and at room temperature (25°C -35°C). The reaction was maintained for 3 hrs. After the completion of the reaction, the catalyst was filtered and then the filtrate was concentrated to in presence of citric acid (0.1 gm).In the residue obtained IPA (400 ml) was added and stirred at 25-35°C for 2 hrs. The precipitated material was filtered and washed with IPA (50 ml) to get the product.
Yield: 62 gm
HPLC: Purity: 99.5 %

Part-B: Ropinirole Hydrochloride pure

Ropinirole Hydrochloride crude (60 gm) was dissolved in 600 ml of water containing citric acid (0.1 gm) and adjusted the pH 8 – 9 using 20 % aqueous sodium carbonate solution. The compound was extracted with dichloromethane. The dichloromethane layer was concentrated to get Ropinirole Base as oil (48 gm). Ropinirole base was dissolved in acetonitrile, water and then Concentrated HCl (21.5 ml) was added at 10-20°C. The crystallized material was stirred for 2 hrs at 5-10°C, filtered to get Ropinirole Hydrochloride.
Yield: 40 gm.
HPLC: 99.97 %,
3-Oxo impurity: 0.01 %.

WE CLAIM:

1. A process for the preparation of ropinirole and its pharmaceutically acceptable salt, the process comprising
a) hydrogenation of NDPA HCl of Formula II in presence of 5% Pd/C in methanol and water at room temperature.

Formula II
b) removal of solvent from the reaction mixture of step a) in presence of antioxidant.
c) isolating Ropinirole hydrochloride from the reaction mixture thereof.
2. The process of claim 1 wherein, step (a) is performed at 10-12 kg hydrogen pressure
3. The process of claim 1 wherein, anti oxidants are one or more of butyated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), Sodium dithionite, Sodium metabisulphite and citric acid.
4. The process of claim 3 wherein, the antioxidant is citric acid.
5. The process of claim 1 wherein, Ropinirole hydrochloride is isolated by adding of isopropanol.
6. The process of Claim 5 wherein, isolation techniques involve such as filtration, decantation, centrifugation and drying.
7. A process the purification of ropinirole hydrochloride having 3-oxo impurity up to 0.2% or more to ropinirole hydrochloride with 3-oxo impurity 0.02% or less the process comprising;
a) contracting Ropinirole hydrochloride having 3-oxo impurity up to 0.15% with water,
b) adjusting pH of solution between 7.5 to 10.5 with suitable base in presence of antioxidants,
c) extracting Ropinirole base in halogenated solvent,
d) isolating pharmaceutically acceptable salt of Ropinirole having 3-oxo impurity 0.02% or less.
8. The process of claim 7 wherein, base is aqueous solution of carbonate, bicarbonate, hydroxide of alkali metal likes sodium and potassium.
9. The process of claim 8 wherein, halogenated solvent is one or more chloroform, dichloromethane, ethylene dichloride.
10. The process of claim 7 wherein, the antioxidant is citric acid.

Dated this 30th day of September 2010
For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory