FIELD OF THE INVENTION
The field of the invention relates to the preparation of pure ropinirole Formula I or salt thereof
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BACKGROUND OF THE INVENTION
Ropinirole hydrochloride is useful in the treatment of Parkinsons disease and is chemically known as 4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone hydrochloride.
Ropinirole and its pharmaceutically acceptable salts were first disclosed in US patent 4,452,808. In general, the synthetic approach reported in the literature for the preparation of Ropinirole or salts involves the reduction of 2-nitro-6-(2-di-n-propylaminoethyl)-phenylacetic acid hydrochloride of Formula II in ethanol using 5% palladium on carbon followed by in situ cyclization.
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There are significant drawbacks to this approach. We have found that reduction of nitro group of 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acid hydrochloride of
formula II to the corresponding amino compound, namely 2-amino-6-(2-di-n-propylaminoethyl)-phenylacetic acid of Formula III or salt thereof,
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does not go to completion under the specified reaction conditions and further conversion to ropinirole results in the formation of many impurities. We have prepared and characterized the following impurities which are present in substantial amounts along with other unidentified impurities that are difficult to remove: a) 4-[2-(n-Propylamino)-ethyl]-2(3H)-indolone or salt thereof
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b) 2-Amino-6-(2-di-n-propylaminoethyl) phenylacetic acid or salt thereof
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c) 4-[2-(Di-n-propylamino)ethyl]-2(3-ethyl)indolone or salt thereof
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These impurities are further carried over to ropinirole, and are difficult to remove even after using 100 times by volume of acetonitrile for recrystallization, thereby making the process uneconomical and unviable.
Our co-pending application 1920/DEL/2005 discloses an improved process over the drawbacks sited above. This application discloses the reduction of nitro compound of Formula II to corresponding amino compound of Formula II and cyclizing the resulting amino compound in situ using palladium on carbon in the presence of aqueous alcoholic medium. After completion of reaction, solvent is removed under vaccum. Although this process is efficient at laboratory scale, but during scale up reactions we have found reaction takes long hours to go to completion even after extended period of time. Reaction has to be continued at higher temperature 50-60°C which leads to formation of impurities at industrial scale and requires purification.
In view of the above, the prior art approaches are not suitable from commercial point of view since the desired ropinirole hydrochloride is not obtained in high purity and requires purification by tedious and cumbersome purification processes. The inventors have observed that during the cyclization of amino compound of formula III, reaction takes longer time at higher temperature which leads to formation of impurities which are very difficult to remove from ropinirole.
In order to achieve a high efficiency of the reaction for industrial synthesis of ropinirole, it is necessary to fasten the cyclization reaction and to avoid the solvent distillation to minimize the formation of impurities.
Thus, the present invention provides a process for the preparation of pure ropinirole by carrying out reduction and cyclization reaction in water without using any organic solvent at industrial scale. Thus process is avoiding use of alcoholic solvents and hence process is cost effective and environment friendly.
SUMMARY OF THE INVENTION
Accordingly, in another general aspect there is provided a process for the preparation of substantially pure ropinirole or a salt thereof. The process includes reducing nitro compound of Formula II
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with a hydrogen gas in the presence of a catalysts in water to produce amino derivative of Formula III,
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cyclizing the resulting amino derivative in situ and isolating the substantially pure ropinirole or a salt thereof by simple isolation method of extraction and acid base treatment.
In one general aspect there is provided highly pure ropinirole or a salt thereof.
In another general aspect there is provided substantially pure ropinirole or a salt thereof containing amino compound is less than 0.05%.
In another general aspect there is provided pure ropinirole or a salt thereof having impurity (a) and (c) each less than 0.05%.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
DETAILED DESCRIPTION OF THE INVENTION
The inventors have developed an efficient process for the preparation of substantially pure ropinirole or a salt thereof by reducing nitro compound of Formula II with a hydrogen gas in the presence of a catalysts in water to produce amino deivative, 2-amino-6-(2-di-n-propylaminoethyl)-phenylacetic acid of Formula III or its salts and cyclizing in situ the amino derivative of Formula III and isolating substantially pure ropinirole or a salt thereof by simple isolation method of extraction and acid base treatment.
In general, nitro compound of Formula II can be prepared by the methods reported in the prior art. Specifically, the nitro compound is prepared by reacting 2-methyl-3-nitro-phenylethyl-A'',;V-di-n-propyl amine with diethyloxalate in the presence of potassium metal in a mixture of tetrahydrofuran and alcoholic solvent to afford ethyl-6-(2-di-n-propylamino ethyl)-2-nitrophenyl pyruvate. The resulting ethyl-6-(2-di-n-propylamino ethyl)-2-nitrophenyl pyruvate is hydrolysed using aqueous hydrogen peroxide solution in the presence of base such as sodium hydroxide or potassium hydroxide.
In general, the 2-nitro-6-(2-di-n-propylaminoethyl)phenylacetic acid hydrochloride of formula II may be reduced with hydrogen gas in the presence of a catalysts in water. The reaction is performed in an autoclave at a temperature between 15° -40°C under hydrogen pressure of 2-6 kg/cm2 for 6-9 hours. The progress of reaction is monitored by HPLC.
The catalyst is selected from group such as palladium on carbon, and platinum on carbon, Raney nickel and the like preferably palladium on carbon is used.
Specifically the reaction is conducted at 15° -40 °C under hydrogen pressure of 2-6 kg/cm in the presence of palladium on carbon using water as solvent and it takes about 8 hours for completion of reaction. At lower temperature of 5-10 °C, under hydrogen gas pressure of 4 kg cm"2 approx 18-24 hours are required for the completion of the reaction. After completion of reaction, catalyst is filtered and the filterate is basified with sodium hydroxide. The reaction mixture is extracted twice or thrice with organic solvent such as isopropyl ether, ethyl acetate and chlorinated solvent such as methylene chloride, chloroform and the like. The combined organic extract is distilled and the resulting ropinirole is purified via its conversions as a hydrochloride or its salts using alcoholic solvent such as methanol, ethanol and the
like to remove inorganic salts. Further ropinirole hydrochloride is optionally purified using acetone and alcoholic solvents.
The hydrochloride salt of Ropinirole is prepared by treating ropinirole with ethanolic-HC1 at ambient temperature. The product is isolated in high purity and high yield. The compound can be optionally given acid base treatment to improve colour and quality if required. The product so obtained displays purity greater than 99.5% by HPLC, and preferably greater than 99.8%. The major advantages realized in the present invention are that process is cost effective and environment friendly as it avoids the use of any organic solvent during reduction and cyclization reactions. No costly solvents are used for recrystallization of ropinirole hydrochloride.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to 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.
Examples
Preparation of Ethyl-6-(-2-di-n-propyIaminoethvn-2-nitro phenyl pyruvate
Potassium metal (11 kg) was added to a mixture of THF (100 L) and absolute alcohol (44 L) in lots (3 - 4 Hours.) at 25°-35°C. The reaction mixture was stirred till potassium metal was completely dissolved. Diethyl oxalate (30.0 kg) was added under nitrogen atmosphere in 30 - 45 min, followed by the addition of 2-methyl-3-nitrophenylethyl-W, A^-di-n-propylamine (50 kg) in 30 - 45 min. at 30° - 35°C. The reaction mass was stirred till 2-methyl-3-nitrophenylethyl-Af jV-di-n-propylamine was consumed. The solvent was recovered under vacuum at 30 - 35°C and then ethyl acetate was added to the residue and pH was adjusted with dilute hydrochloric acid to

6.5 - 7,0 at 10° - 15 °C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2). Combined organic layer was distilled under vacuum at temp. 35° - 40°C and cool to 20° - 25°C. n-Hexane (150 L) was added to the residue and the reaction mixture was stirred slowly for 30 min at 20° - 25°C. The crystalline product thus obtained was filtered and washed with n-hexane (2x50 L). The product was air dried to obtain 52 kg of title compound having purity of 98.20% by HPLC.
Preparation of 2-Nitro-6-(-2-di-n-propyiaminoethyI) phenyl acetic acid hvdrochloride
To a stirred solution of sodium hydroxide (7.9 kg, 197.50 mol) in demineralized water (375 L), ethyl-6-(-2-di-n-propylaminoethyl)-2-nitro phenyl pyruvate (25.0 kg, 68.68 mol) was added and the reaction mass was stirred for 60 min at 15-20°C. After completion of reaction, the reaction mass was cooled to 0-2°C and 30% hydrogen peroxide solution (3.95 L, 110.3 moles) was added quickly. The reaction mass was stirred for about 10 minutes at 10-15°C and saturated sodium bisulphite solution (approx 50 % solution, 8.0-9.0 L) was added at 0-5°C to quench the excess hydrogen peroxide present in the mixture (HCl/Starch/KI test indicated the absence of peroxide). The reaction mixture was extracted with ethyl acetate (2 x 75.0 L), the layers were separated. To the aqueous layer, concentrated hydrochloric acid (-23-25 L) was added slowly to adjust pH 2.0-3.0. Solid sodium chloride (175.0 kg) was added under stirring (to saturate the reaction mass) followed by addition of n-hexane (75.0 L) and the reaction mass was stirred for 30-40 min at 5-10°C.
The solid thus precipitated was filtered, washed with n-hexane (50 L) and dried under vacuum at 65-70°C to give the crude product as a light brown solid. The crude product was dissolved in methanol (250 L) and filtered to remove the undissolved inorganic salts. Methanol was distilled out completely and the residue was then dissolved in acetone (75.0 L) which upon complete recovery again provides light

brown solid. The product was suspended in ethyl alcohol (75.0 L), the temperature was raised to 40-45°C, stirred for 30-40 min and then cooled to 0-5°C. The reaction mass was further stirred for 30-40 min at 0-5°C, filtered and washed with chilled ethyl alcohol (25.0 L). The product was dried at 60- 65 °C under vacuum for 6-8 hrs to afford the title compound as a white to off white crystalline solid. Yield 17.5 kg (73.03%). Purity (HPLC) 99.15 %.
Preparation of 2-Nitro-6-(-2-di-n-propylaminoethyl) phenyl acetic acid hydrochloride
To a stirred solution of sodium hydroxide (23.70 g, 0.59 mol) in water (1.125 L), ethyl-6-(-2-di-n-propylaminoethyl)-2-nitro phenyl pyruvate (75.0 g, 0.206 mol) was added and the reaction mass was stirred for 60 min at 5-10°C. After completion of reaction, (nitro phenyl pyruvate derivative < 0.5% by HPLC analysis.) the reaction mass was cooled to 0-2°C and hydrogen peroxide solution (30% solution, 23.35 ml) was added slowly while keeping the temperature at 0 - 5 °C. The reaction mass was stirred at 0-5°C till completion of reaction (keto acid < 1.0% by HPLC analysis). Saturated sodium bisulphite solution (-75 ml) was added to adjust pH 9.0 -9.5 and the mixture was extracted with ethyl acetate (2 x 225 ml) and layers were separated. To the aqueous layer, concentrated hydrochloric acid was added to adjust pH to 2.0-3.0. Solid sodium chloride (525 g) was added under stirring followed by addition of n-hexane (225 ml) and the reaction mass was stirred for 30-40 min at 5-10°C. The resulting solid along with the salt was filtered, slurry washed with n-hexane (75 ml) and dried under vacuum at 65-70°C to give the crude product as a light brown solid. The crude product was dissolved in methanol (750 ml and filtered to remove the undissolved inorganic salts. Methanol was distilled out completely under vacuum at 40-45°C and the residue was then dissolved in acetone (225 ml). Complete recovery of acetone under vacuum provided light brown residue to which additional amount of acetone (187.5 ml) was added, the mixture was cooled to 0-5°C, stirred for 60 min, filtered and slurry washed with acetone (75 ml) and suck dried for 1 hr. The product

was suspended in absolute ethyl alcohol (225 ml), the temperature was raised to 40-45°C, stirred for 30-40 min and then cooled to 0-5°C. The reaction mass was stirred for 30-40 min at 0-5°C, filtered, washed chilled ethyl alcohol ( 75 ml) and dried at 60-65 °C under vacuum for 6-8 hours to afford 2-nitro-6-(-2-di-n-propylaminoethyl) phenyl acetic acid hydrochloride as a white to off white crystalline solid. Yield: 63.75 g, (89%). Purity (HPLC) 99.30 %.
Preparation of Roninirolc hvdrochloride
To a stirred solution of 2-nitro-6-(-2-di-n-propylaminoethyl) phenyl acetic acid hydrochloride (20 gm) in demineralized water (800 ml), Pd/C (10% , 2.5 g) was added and the reaction mixture was subjected to 4.0 kg/cm2 hydrogen gas pressure. The reaction mixture was then stirred at 30-35 °C maintaining 4.0 kg/cm2 hydrogen gas pressure for 8 hrs. After completion of the reaction, the reaction mass was filtered through hyflo bed and filtered catalyst was washed with demineralized water (40 ml). The filtrate was basified with 4% sodium hydroxide solution to adjust pH to 10-11 and the reaction mixture was extracted with isopropyl ether (2 x 100ml). The combined organic layer was washed with water (40 ml) and dried over sodium sulphate. Complete recovery of the solvent under vaccum provided dark colored oil to which absolute ethyl alcohol (20 ml) was added and the solvent was recovered under vacuum at 35-40 °C. The residue was dissolved in absolute ethyl alcohol (100 ml), and the reaction mass was cooled to 0-5°C and ethanolic HC1 (-25-28%) was added slowly to adjust pH to 2.0-3.0. The precipitated solid was stirred for 30-40 min at 15-20 °C, filtered and washed with chilled ethanol (20 ml) and dried to afford Ropinirole hydrochloride. Yield 15.0 g (87.2%); Purity (HPLC) 99.65%.

Crystallization of Ropinirole hyydrochloridc
To a stirred suspension of isopropyl ether (140 ml), water (34 ml), 4% sodium hydroxide solution (70 ml) crude ropinirole hydrochloride (14.0 g) was added at 15-20 °C and after stirring for 30-40 min, the layers were separated. Aqueous layer was extracted with isopropyl ether (2 x 70 ml), the combined organic layer was washed with water (30 ml). The separated isopropyl ether layer was dried over sodium sulphate. The solvent was removed under vacuum to obtain ropinirole oily liquid (12.5g), which was dissolved in isopropyl ether (125 ml) and the reaction mass, was cooled to 5-10 °C. To this ethanolic HCI (~ 22-25%) was added slowly to adjust pH to 2.0-3.0, stirred for 30-40 minutes at 15-20 °C, filtered and washed with chilled isopropyl ether (25ml). The product was dried at 65-70 °C under vacuum for 24 hours to give ropinirole hydrochloride as a white crystalline solid. Yield: 12.2g. Purity (HPLC) 99.85%.

WE CLAIM:
1. An improved process for the preparation of Ropinirole of Formula I or salt thereof,
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which comprises reducing nitro compound of Formula II, or salt thereof,
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with a hydrogen gas in the presence of a catalysts in water to produce amino compound of Formula III, or salt thereof,
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cyclizing the resulting amino compound in situ,
filtering the catalyst,
treating the filtrate with dilute sodium hydroxide solution, extracting the reaction mixture with suitable organic solvent, distilling off the organic solvent and
treating the resulting ropinirole with ethanolic-hydrochloric acid to prepare Ropinirole hydrochloride.
2. The process according to claim 1 wherein reaction is conducted at a temperature of
10°-40°C.
3. The process according to claim 1 wherein reaction is preferably conducted at a
temperature of 20° -30°C.
4. The process according to claim 1 wherein catalyst is palladium on carbon, and
platinum on carbon or Raney nickel.
5. The process according to claim 4 wherein catalyst is preferably palladium on
carbon.
6. The process according to claim 1 wherein suitable organic solvent is isopropyl
ether, ethyl acetate and chlorinated solvents such as methylene chloride,
chloroform or mixture thereof.