WO2008084499A1

WO2008084499A1 - An industrial process for the preparation of pure ropinirole

Info

Publication number: WO2008084499A1
Application number: PCT/IN2008/000008
Authority: WO
Inventors: Gurdeep Singh Sarin; Chidambaram Venkateswaran Srinivasan; Lalit Wadhwa
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2007-01-10
Filing date: 2008-01-09
Publication date: 2008-07-17

Abstract

The present invention relates to highly pure ropinirole or salt thereof and a process for preparing highly pure ropinirole of structural formula (I): by reducing nitro compound of formula (II): with a hydrogen gas in the presence of a catalyst in water to produce amino compound and cyclizing the resulting amino compound in situ.

Description

AN INDUSTRIAL PROCESS FOR THE PREPARATION OF PURE ROPINIROLE'

FIELD OF THE INVENTION

The field of the invention relates to the preparation of pure ropinirole of formula I or salt thereof

Formula I

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)-phcnylacetic acid hydrochloride of formula II in ethanol using 5% palladium on carbon followed by in situ cyclization.

Formula II

There are significant drawbacks to this approach. We have found that reduction of nitro group of 2-nitro-6-(2-di-n-propylaminoethyl)-phenyI 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,

Formula III

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 are difficult to remove:

a) 4-[2-(n-Propylamino)-ethyl]-2(3-H)-indolone or salt thereof

Formula IV b) 2-Amino-6-(2-di-n-propylaminoethyl)-phenylacetic acid or salt thereof

Formula III

c) 4-[2-(Di-n-propylamino)-ethyl]-2(3-ethyl)-indolone or salt thereof

d) 4-[2-(Di-n-propylamino)-ethyl] lH-indole-2,3-dione

Formula VI

These impurities are further carried over to ropinirole, which are difficult to remove even after using 100 times by volume of acetonitrile for recrystallization, therby 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 50-60⁰C which leads to formation of impurities at industrial scale and require purification.

In view of the above, the prior art approaches are not suitable from commercial point of view since the desired ropinirole 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 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

Formula II

with a hydrogen gas in the presence of catalyst in water to produce amino derivative of formula HI ,

Formula III

cyclizing the resulting amino compound 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 a highly pure ropinirole or a salt thereof.

In another general aspect there is provided substantially pure ropinirole or a salt thereof having amino compound 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 catalyst in water to produce amino derivative, 2-amino-6-(2-di-n- propylaminoethyl)-phenylacetic acid of formula III or its salts and cyclizing in si 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-N,N- 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-nitrophcnyl pyruvate is hydrolysed using aqueous hydrogen peroxide solution in the presence of base such as sodium hydroxide, potassium hydroxide and the like.

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 catalyst in water. The reaction is performed in an autoclave at a temperature between 15° -4O⁰C under hydrogen pressure of 2-6 kg/cm² for 6-9 hours. The progress of reaction is monitored by high performance liquid chromatography (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/cm² 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 ⁰C, under hydrogen gas pressure of 4 kg/cm², 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 is optionally purified using acetone and alcoholic solvents.

The hydrochloride salt of Ropinirole is prepared by treating ropinirole with ethanol ic- hydrochloride 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 is having purity greater than 99.5% by HPLC, and preferably greater than 99.8%. The major advantages realized in the present invention are tl 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 EthyI-6-(-2-di-n-propylaminoethyI)-2-nitro phenyl pyruvate

Potassium metal (1 lkg) was added to a mixture of tetrahydrofuran(100 It.) and alcohol (44 It.) in lots (3-4 hours) at 25 °C-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 minutes, followed by the addition of 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine (50 kg) in 30-45 minutes at 30-35⁰C. The reaction mass was stirred till 2-methyl-3- nitrophenylethyl-N, N-di-n-propylamine was consumed. The solvent was recovered under vacuum at 30-35 ⁰C and then ethyl acetate was added to the residue and pH was adjusted with dilute hydrochloric acid to 6.5 - 7.0 at 1O⁰C - 15⁰C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2). Combined organic layer was distilled under vacuum at a temperature of 35-4O⁰C and cooled to 20-25⁰C. n-Hexane (150 It.) was added to the residue and the reaction mixture was stirred slowly for 30 minutes at 20-25⁰C. The crystalline product thus obtained was filtered and washed with n-hexane (2x50 It.). The product was air dried to obtain 52 kg of title compound having purity of 98.20% by HPLC.

Preparation of 2-Νitro-6-(-2-di-n-propylaminoethyl) phenyl acetic acid hydrochloride

To a stirred solution of sodium hydroxide (7.9 kg, 197.50 mol) in demineralized water (375 It), ethyl-6-(-2-di-n-propylaminoethyl)-2-nitiO phenyl pyruvate (25.0 kg, 68.68 mol) was added and the reaction mass was stirred for 60 minutes at 15-20°C. After completion of the reaction, the reaction mass was cooled to 0-2⁰C and 30 % hydrogen peroxide solution (3.95 It., 1 10.3 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 It) was added at 0-5°C to quench the excess hydrogen peroxide present in the mixture (The HCl/Starch/KI test indicate of peroxide). The reaction mixture was extracted with ethyl acetate (2 x 75.0 It), the layers were separated. To the aqueous layer, concentrated hydrochloric acid (-23-25 It) 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 It) and the reaction mass was stirred for 30-40 minutes at 5-10°C. The solid thus precipitated was filtered, washed with n- hexane (50 It.) 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 It.) and filtered to remove the undissolved inorganic salts. Methanol was distilled out completely and the residue was then dissolved in acetone (75.0 It.) which upon complete recovery again provide light brown solid. The product was suspended in ethyl alcohol (75.0 It.), the temperature was raised to 40-45 °C, stirred for 30-40 minutes and then cooled to 0-5°C. The reaction mass was further stirred for 30-40 minutes at 0-5°C, filtered and washed the product with chilled ethyl alcohol (25.0 It.). The product was dried at 60- 65 °C under vacuum for 6-8 hours to afford 17.5 kg of the title compound as a white to off white crystalline solid having purity of 99.15% by HPLC. (Yield 73.03%).

Preparation of 2-Nitro-6-(-2-di-n-propyiaminoethyI) phenyl acetic acid hydrochloride

To a stirred solution of sodium hydroxide (23.70 g, 0.59 mol) in water (1.125 It.), 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 minutes at 5-10°C. After completion of reaction, ( nitro phenyl pyruvate derivative < 0.50%. by HPLC analysis) the reaction mass was cooled to 0-2⁰C and hydrogen peroxide solution (30% solution, 23.35 ml) was added slowly while keeping the temperature at 0 - 5 ⁰C. The reaction mass was stirred at 0-5⁰C 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 minutes 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 0-5⁰C, stirred for U 60 minutes, filtered and slurry washed with acetone (75 ml) and suck dried foi product was suspended in absolute ethyl alcohol (225 ml), the temperature was raised to 40- 45⁰C, stirred for 30-40 minutes and then cooled to 0-5°C. The reaction mass was stirred for 30- 40 minutes 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 63.75 g of the title compound as a white to off white crystalline solid having purity of 99.30% by HPLC. (Yield:89%).

Preparation of Ropinirole hydrochloride

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 ⁰C maintaining 4.0 kg/cm² hydrogen gas pressure for 8 hours. After completion of the reaction, the reaction mass was filtered over 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 10-1 1 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 vacuum provided dark colored oil to which absolute ethyl alcohol (20 ml) was added and the solvent was recovered under vacuum at 35-4O⁰C. The residue was dissolved in absolute ethyl alcohol (100 ml), and the reaction mass was cooled to 0-5⁰C and ethanolic hydrochloride (-25-28%) was added slowly to adjust pH to 2.0-3.0. The precipitated solid was stirred for 30-40 minutes at 15-2O ⁰C, filtered and washed with chilled ethanol (20 ml) and dried to afford 15.0 g of ropinirole hydrochloride having purity of 99.65% by HPLC. (Yield :87.2%)

Crystallization of Ropinirole hydrochloride

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 15-20⁰C and after stirring for 30-40 minutes, 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 as oily liquid (12.5g), which was dissolved in isopropyl ether (125ml) and the reaction mass, was cooled to 5-10 ⁰C. To this ethanolic hydrochloride (~ 22-25%) was added slowly to adjust pH to 2.0-3.0, stirred for 30-40 minutes at 15-2O⁰C, filtered and washed with chilled isopropyl ether (25ml). The product was dried at 65-7O⁰C under vacuum for 24 hours to give 12.2g of ropinirole hydrochloride as a white crystalline solid having purity of 99.85% by HPLC.

Claims

WE CLAIM:

1. An improved process for the preparation of Ropinirole of formula I or salt thereof,

Formula I

which comprises reducing nitro compound of formula II, or salt thereof,

Formula II

with a hydrogen gas in the presence of a catalyst in water to produce amino compound of formula III, or salt thereof,

Formula III

cyclizing the resulting amino compound in situ,

filtering the catalyst, treating with dilute sodium hydroxide solution, extracting the reaction mixture with suitable organic solvent, distilling the organic layer, treating the resulting ropinirole with ethanolic-hydrochloride to prepare ropinirole hydrochloride.

2. The process according to claim 1 wherein reaction is conducted at a tempei 40⁰C.

3. The process according to claim 1 wherein reaction is preferably conducted at a temperature of 20° -30⁰C.

4. The process according to claim 1 wherein reaction is preferably conducted under hydrogen gas pressure of 2-6 kg/cm".

5. The process according to claim 1 wherein catalyst is selected from palladium on carbon, platinum on carbon or Raney nickel.

6. The process according to claim 4 wherein catalyst is preferably palladium on carbon.

7. The process according to claim 1 wherein suitable organic solvent is selected from isopropyl ether, ethyl acetate and chlorinated solvents such as methylene chloride, chloroform or mixture thereof.

8. The process according to claim 1 which further comprises optionally purifying ropinirole hydrochloride or its salts using alcoholic solvent such as methanol, ethanol and the like.

9. The process according to claim 1 which further comprises optionally purifying ropinirole hydrochloride or its salts using acetone and alcoholic solvents.