FILED OF THE INVENTION
The present invention relates to an improved process for the preparation of 2-nitro-6-(2-di-n-propylaminoethyl)-phenylacetic acid of formula I or its salts, an intermediate in the preparation of an indolone derivative namely Ropinirole of Formulall.
(Formula Removed)
Formula II BACKGROUND OF THE INVENTION
Ropinirole of Formula II is a useful in the treatment of Parkinsons disease, and chemically known as 4-[2-(di-n-propylamino)-ethyl]-2(3H)-indolone.
Ropinirole has been first disclosed in US patent 4,452,808. In general, synthetic approach reported in US 4,452,808 for the preparation of Ropinirole is shown in Scheme-1.
(Scheme Removed)
The preparation of 2-nitro-6-(2-di-n-propylaminoethyl)-phenylacetic acid of formula I is earned out staring from 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine of Formula III.
In exemplified process, 2-niethyl-3-nitrophenylethyl-N,N-di-n-propylamine is treated with sodium metal in absolute ethanol and diethyl oxalate in alcohol and about 60-70% of unreacted starting material is collected after workup which has been recycled three times resulting in overall yield of 46%.
Thereafter the resulting compound is hydrolysed using base and hydrogen peroxide and compound of formula I is isolated as hydrochloride salt. The reaction mixture is treated with concentrated hydrochloric acid and the aqueous acidic solution was concentrated to isolate the solid product. During concentration of aqueous acidic solution, the product may decompose which results in low yields.
To achieve a high efficiency of the reaction for industrial process of Ropinirole, it is necessary that reactions should go to completion to avoid separation of starting material and improve the yields and purity.
Therefore there is an urgent need to provide simple and efficient process for the preparation of intermediates in high yield and purity which can be used to prepare highly pure Ropinirole.
Thus, the present invention provides a sample and industrially advantageous process for the preparation of 2-nitro-6-(2-di-n- propylaminoethyl)-phenylacetic acid in high yield and high purity.
SUMMARY OF THE INVENTION
The present invention relates to an industrially advantageous process for the preparation of 2-nitro-6-(2-di-n-propylaminoethyl)-phenylacetic acid of formula I or a salt thereof,
(Formula Removed)
The process comprises: reacting 2-methyl-3-nitrophenylethy]-N,N-di-n-propylamine of Formula III,
(Formula Removed)
with potassium or sodium metal in a alcoholic solvent containing tetrahydrofuran, diethyl oxalate, at a temperature of 20°- 55°C to prepare a compound of Formula IV, ethyl-6-(2-di-n-propylaminoethyl)-2-nitrophenylpyruvate having a compound of Formula V in 2-30% ratio.
(Formula Removed)
hydrolyzing the compound of Formula IV containing formula V, under basic conditions in the presence of hydrogen peroxide,
adjusting pH of reaction mixture to 2-3 using concentrated hydrochloric acid, saturating the aqueous layer with sodium chloride,
isolating the precipitated compound, 2-nitro-6-(2-di-n-propylaminoethyl)-phenylacetic acid hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to improved process for the preparation of substantially pure Ropinirole or a salt thereof, by reacting 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylainme of Formula III with diethyl oxalate in the presence of potassium metal in a mixture of tetrahydrofuran and alcoholic solvent. In general, potassium metal may be taken in a mixture of tetrahydrofuran and alcohol, followed by addition of diethyl oxalate and 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylamine. Generally the reaction is conducted at a temperature of 20°- 55°C and preferably at 30°- 45°C. After completion of reaction, it is advantageous to adjust the pH of the reaction mass to 6.0-7.0 and
preferably 6.5-7.0. The product can be isolated in suitable organic solvent such as ethyl acetate and preferably ethyl acetate is used.
The solvent is removed and ethyl-6-(2-di-n-propylaminoethyl)-2-nitrophenyl pyruvate is isolated in high yields 80-85% without recycling of starting material. Ethyl-6-(2-di-n-propylaminoethyl)-2-nitrophenylpyruvate of formula IV is not a single compound it contains a compound of formula V in 2-30% ratio.
(Formula Removed)
It can be used as such in the next step without separation as hydrolysis of both product leads to the required compound of formula I.
Specifically, hydrolysis is earned out using hydrogen peroxide in the presence of base such as sodium hydroxide, potassium hydroxide, ammonia and the like and preferably sodium hydroxide is used. The reaction is carried out at ambient temperature and it takes about 1-3 hours for completion. The pH of reaction mass is adjusted to 9.0-9.5 using mineral acid such as hydrochloric acid and optionally the aqueous layer is washed with organic solvent such as ethyl acetate. Thereafter hydrochloric salt is prepared using hydrochloric acid and pH is adjusted between 2 to 3. The reaction mass is saturated with sodium chloride and diluted with hexane. The hydrochloride salt separates out in high yield having high purity more than 97%.
In another embodiment of the present invention, the compound of formula I is prepared in high purity (greater than 98.8%) from 2-methyl-3-nitrophenylethyl-N,
N-di-n-propylamine of Formula III in single step without isolating the compound of formula IV. Specifically 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine of Formula III is treated with diethyl oxalate in the presence of potassium metal in tetrahydrofuran and ethanol. The progress of the reaction is monitored by TLC. After completion of reaction, solvent is removed and residue is dissolved in chilled water. It is advantageous to wash aqueous layer with n-hexane to recover unreacted 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine if present and can be recycled. Thereafter aqueous layer is hydrolysed using hydrogen peroxide at a temperature of 0°-10°C. After completion of reaction which is monitored by HPLC, nitro compound is isolated as hydrochloride salt using isolation process as discussed above. The major advantages realized in the present invention are:
• High yield and high purity
• Simple process without multiple recycling of the starting material.
• Preparation of HC1 salt of 2-nitro-6(2-di-n-propylammoethyl)-
phenylacetic acid by simple isolation technique i.e. extraction and
precipitation and avoiding distillation of highly acidic aqueous solution.
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.
Example 1
Step-I
Preparation of Ethyl-6-(-2-di-n-propylaminoethyl)-2-nitrophenylpyruate
Potassium metal (33 g) was added to a mixture of THF (200 ml) and absolute alcohol (132 ml) in lots (3-4 Hrs.) at 25°-35°C. The reaction mixture was stirred
till potassium metal was completely dissolved. Diethyl oxalate (90 g) was added under nitrogen atmosphere in 30 - 45 min, followed by the addition of 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine (150 g) in 30 - 45 min. at 30° - 35°C. 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°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 x 450 ml). Combined organic layer was distilled under vacuum at temp. 35° - 40°C and cool to 20° - 25°C. n-Hexane (450 ml) 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 (2 x 150 ml). The product was air dried to obtain 156 g (yield 75.72 %) of title compound having purity of 97.39% by HPLC.
Step-II
Preparation of 2-Nitro-6(2-di-n-propylaminoethyl) phenylacetic acid hydrochloride
Ethyl-6-(2-di-n-propylaminoethyl)-2-nitrophenyl pyruvate (150 g) was added to sodium hydroxide solution (47 g in 2.25 lit of D.M. Water) and was stirred for 1 hour at 20° - 25°C. The reaction mass was cooled to 0±2°C, and hydrogen peroxide was added (75 ml) slowly (20-30 min.) at 0° - 8°C. The reaction mass was stirred at 20° - 25°C till keto acid present was NMT 1.0% by HPLC, Thereafter pH was adjusted slowly to 9.0 - 9.5 with cone, hydrochloric acid and ethyl acetate (450 ml) were added with stirring (10-15 min) at 20° - 25°C, The organic layer was separated and the aqueous layer was extracted with ethyl acetate (450 ml). The pH of aqueous was adjusted to 2.0 - 3.0 with cone, hydrochloric acid (133 ml) and stirred for 15 minutes followed by addition of sodium chloride (800 g). The reaction mass was stirred for 60 - 90 min. and n-
hexane (300 ml) was added and stirred further for 30-40 minutes at 20° - 25°C. The suspended product thus obtained was filtered and washed with n-hexane (300 ml). The product was dried and dissolved in methanol (1.5 lit) at 45° -50°C and filtered at 35° -40°C to remove traces of sodium chloride. The methanol was distilled and crude product, thus obtained was recrystallized twice from acetone and alcohol successively to obtain 104 g (75.53%) of title compound having purity of 98.25% by HPLC.
Example 2
Preparation of 2- Nitro-6-(-2-di-n-propylaminoethyl) phenylacetic acid hydrochloride
Potassium metal (11 g) was added to a mixture of THF (100 ml) and absolute alcohol (44 ml) in lots (3-4 hrs) at 25° -35°C. The reaction mixture was stirred till potassium metal completely dissolved. Diethyl oxalate (31 g) was added under nitrogen atmosphere in 30 - 45 min, followed by the addition of 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine (50 g) in 30 - 45 min. at 30° -35°C. The reaction mass was stirred for 3-4 h at 30° -35°C and its reaction was monitored by TLC. The solvent was recovered under vacuum at 30° - 35°C. The reaction mass was cooled to 10° - 15°C followed by addition of chilled water (75 ml) and stirred for 1.0 hour at 20° - 25°C. Thereafter reaction mass was washed with n-hexane (2x25ml) and cooled to 0° -2°C. To reaction mass, hydrogen peroxide (23 ml, 50 % w/w) was added slowly maintaining the reaction temperature 0° -10UC. Thereafter temperature of reaction was raised to 20° - 25 °C and stirred at 20° -25°C till keto acid presence was NMT 1.0% by HPLC. The pH of the solution was adjusted to 2.0 - 3.0 with concentrated hydrochloric acid (45 ml) and stirred for 15 minutes followed by addition of sodium chloride (198 g). The reaction mass was stirred for 60 - 90 minutes and n-hexane (25ml) was added and stirred for 30-40 minute at 20° - 25°C. The product thus obtained was centrifuged,
washed with n-hexane (100 ml), dried and dissolved in methanol (400 ml) at 45° -50°C and filtered. Methanol was recovered under vacuum at 40° - 45°C and the residue was crystallized with acetone and ethanol successively to obtain 38 g of title compound having purity of 98.84% by HPLC.

WE CLAIM:
1. An industrially advantageous process for the preparation of 2-nitro-6(2-di-n-propylaminoethyl)-phenylacetic acid of formula I or a salt thereof, which is a key intermediate in the preparation of Ropinirole,
(Formula Removed)
comprises reacting 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine of Formula III,
(Formula Removed)
with potassium or sodium metal in a alcoholic solvent containing tetrahydrofuran. diethyl oxalate, at a temperature of 20° -55°C to prepare a compound of Formula IV, ethyl-6-(2-di-n-propylamino ethyl)-2-nitro phenyl pyruvate which contains a compound of Formula V in 2-30% ratio,
(Formula Removed)
hydrolyzing the compound of Formula IV containing formula V, under basic conditions in the presence of hydrogen peroxide,
adjusting pH of reaction mixture to 2-3 using preferably acid, saturating the aqueous layer with sodium chloride,
isolating the salt of 2-nitro-6(2-di-n-propylaminoethyl)-phenylacetic acid preferably hydrochloride.
2. The process according to claim 1 wherein alcoholic solvent is methanol,
ethanol, isopropanol and mixture thereof.
3. The process according to claim 2 wherein alcoholic solvent is ethanol.
4. The process according to claim 1 wherein reaction is conducted at a
temperature of 25° -55°C.
5. The process according to claim 4 wherein reaction temperature is 30° -45°C.
6. The process according to claim 1 wherein 2-nitro-6(2-di-n-propylaminoemyl)-
phenylacetic acid of formula I is converted to 2-nitro-6(2-di-n-propylaminoethyl)-
phenylacetic acid hydrochloride in single step, without isolation of a mixture of
compound of formula IV and compound of formula V.
7. The process according to claim 1 wherein 2-nitro-6(2-di-n-propylaminoethyl)-
phenylacetic acid of formula I is converted to 2-nitro-6(2-di-n-propylaminoethyl)-
phenylacetic acid hydrochloride through isolation of a mixture of compound of
formula IV and compound of formula V.
8. The process according to claim 1 wherein 2-nitro-6-(2-di-n-propylaminoethyl)-phenylacetic acid hydrochloride is converted to Ropinirole.