DESC:RELATED PATENT APPLICATION
This application claims the priority to and benefit of Indian Provisional Patent Application No. 202141029106 filed on June 29, 2021; the disclosure of which are incorporated herein by reference.
FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of rotigotine, which is feasible for plant batches, eco-friendly, and also economically significant.

BACKGROUND OF THE INVENTION

Rotigotine is chemically known as (6S)-6-{propyl [2-(2-thienyl)ethyl]amino}-5,6,7,8-tetrahydro-1-naphthalenol having the formula (I) as mentioned below.

Rotigotine is marketed as Neupro in US and Europe for the treatment of Parkinson's disease. Rotigotine was first disclosed in the U.S. Patent No. 4,564,628.

The U.S. Patent No. 4,564,628 discloses two processes for the preparation of rotigotine. One of the processes is depicted in Scheme-1.

In this scheme-1, the compound 1,2,3,4-tetrahydro-5-methoxy-N-propyl-N-[2-(2-thienyl)ethyl]-2-naphthaleneamine (A) is prepared from the reaction of 1,2,3,4-tetrahydro-5-methoxy-N-[2-(thienyl)-ethyl]-2-naphthaleneamine with propionyl chloride to form an intermediate followed by the reduction of the formed intermediate. The compound 1,2,3,4-tetrahydro-5-methoxy-N-propyl-N-[2-(2-thienyl)ethyl]-2-naphthaleneamine (A) is then demethylated to form racemic rotigotine.

Another process involves the preparation of the intermediate 1,2,3,4-tetrahydro-5-methoxy-N-propyl-N-[2-(2-thienyl)ethyl]-2-naphthaleneamine (A) from the reaction of 1,2,3,4-tetrahydro-5-methoxy-N-propyl-2-naphthaleneamine with 2-thienylacetic acid in the presence of borane trimethylamine complex as depicted in Scheme-2. The prepared intermediate (A) in this process is then demethylated to form rotigotine.

The transformation of intermediate (A) into rotigotine involves the demethylation of compound (A) in the presence of boron tribromide at low temperature in inert solvents. After the completion of this reaction, the excess boron tribromide was destroyed by addition of methanol.

The use of 48% hydrobromic acid for the demethylation of the compound (A) reported in literature, yielded N-dealkylated impurities along with rotigotine. The structural similarity of the impurities and rotigotine makes the purification problematic through physical methods.

The use of boron tribromide for the demethylation of the compound (A) to obtain rotigotine reported in literature, has to be carried out at low temperatures between -30°C and -40°C. Performing reaction at such low temperatures and cumbersome processes involving the treatment of excess of boron tribromide makes this process less preferable on the commercial scale.

The use of aluminium chloride along with thiourea for the demethylation of the compound (A) to obtain rotigotine as disclosed in the International Publication No. 2010073124 results in rotigotine with impurities. These impurities formed at this stage are not easy to purify from rotigotine. Further multiple stages of purification of rotigotine from these impurities causes yield loss in the final API.

The U.S. Patent No. 4,885,308 discloses a process for the preparation of Rotigotine involving the steps of: the resolution of racemic 2-(N-propylamino)-5-methoxytetralin to get desired enantiomer and then converting the desired enantiomer to rotigotine, using the process disclosed in U.S. Patent No. 4,564,628.

The U.S. Patent No. 6,372,920 discloses a process for preparing rotigotine involving the step of: reacting (-)-5-hydroxy-N-n-propyl-2-aminotetralin with 2-(2-thienyl)ethanol toluene sulfonate in the presence of alkali metal carbonate or alkali metal bicarbonate.

The U.S. Patent No. 8,519,160 discloses a process for the preparation of rotigotine involving the steps of: (i) demethylating of 2-N-propyl-5-methoxy tetraline with 48% hydrobromic acid to obtain 2-N-propyl-5-hydroxy tetraline base; and (ii) reacting the obtained 2-N-propyl-5-hydroxy tetraline base with 2-thienylacetic acid-sodium borohydride complex in toluene to obtain rotigotine free base.

Bromo impurities formed during the demethylation of the compound 2-N-propyl-5-methoxy tetraline using 48% hydrobromic acid to obtain 2-N-propyl-5-hydroxy tetraline base are difficult to remove from the obtained 2-N-propyl-5-hydroxy tetraline base.

The U.S. Patent No. 8,614,337 discloses a method for preparing Rotigotine which involves the steps of: (i) resolution of racemic to obtain (S)-5-methoxy-N-2'-(thien-2-yl-)ethyl-tetralin-2-amine; and (ii) reaction of the resolved enantiomer with iodopropane in the presence of a base to yield (S)-5-methoxy-N-propyl-N-(2'-(thien-2-yl-)ethyl)-tetralin-2-amine (A) and (iii) demethylation of the compound (S)-5-methoxy-N-propyl-N-(2'-(thien-2-yl-)ethyl)-tetralin-2-amine (A) to obtain rotigotine.

The US Patent US 10611749 discloses a process for the preparation of rotigotine or its salts thereof: the rotigotine process scheme as given below,

reducing the compound obtained in step (ii) with borane dimethyl sulfide to obtain the compound of rotigotine or its salt thereof. Borane dimethyl sulfide is flammable and reacts readily with water to produce a flammable gas.

The publication Journal of Chemical Society 1970, page no; 1667-74 discloses the reduction of carbonyl group using freshly prepared diborane from sodium borohydride and boron trifluoride.

Besides the availability of different processes for the preparation of rotigotine in state of the art, there is a need for an alternative process for the preparation of rotigotine and its intermediates thereof, which is co-friendly and economically significant than conventional processes used for the preparation of rotigotine.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide an efficient and industry feasible process for the preparation of rotigotine, which is eco-friendly and economically significant.

SUMMARY OF THE INVENTION

Accordingly, there is provided an improved process for the preparation of rotigotine and its intermediates thereof.

Accordingly, in one aspect of the present invention is to provide a process for the preparation of rotigotine of formula (I),

comprising the steps of:
reacting compound (S)-1,2,3,4-tetrahydro-5-methoxy-N-propyl-2-naphthalenamine of formula (IV) or its salt thereof

with 2-thienylacetic acid derivative of formula (V) or its salt thereof,

wherein X represent a leaving group, in the presence of a base in a biphasic solvent system to obtain a compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or its salt thereof;

demethylating the compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or its salt thereof obtained in step (i) with aluminium chloride and thiourea in a solvent to obtain a compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (II) or its salt thereof;

treating the compound of formula (II) obtained in step (ii) with sodium borohydride and boron trifluoride in a solvent to obtain rotigotine of formula (I) or its salt thereof;

optionally liberating the rotigotine free base from the salt obtained in step (iii) in the presence of a base and a solvent; and
isolating rotigotine as a free base from the reaction mass obtained in step (iii) or step (iv).

Accordingly, in one aspect of the present invention, the leaving group is selected from the group comprising of halogens include chlorine, bromine, or iodine, alkylsulfonyloxy, trifluoro methyl sulfonyl oxy, and aryl sulfonyl oxy include benzene sulfonyl oxy and toluene sulfonyl oxy.

Accordingly, in one aspect, the biphasic solvent system used in step (i) comprises a mixture of water and an immiscible organic solvent.

Accordingly, in one aspect, the base used in step (i) is selected from the group comprising of hydroxides, carbonate salts of alkali, alkaline earth metals, and organic bases.

According to still another aspect, the base used in step (i) and step (iv) is selected from the group comprising of lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, and cesium carbonate.

Accordingly, in one aspect, the solvent used in step (iii) is selected from a group comprising of aromatic solvents, nitrile solvents, ether solvents, N,N-dimethylformamide, and mixtures thereof.

According to still another aspect, the solvent used in step (iii) is preferably tetrahydrofuran.

Another aspect of the present invention is to provide a process for the preparation of rotigotine of formula (I),

comprising the step of:

treating the compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (II) or its salt thereof;

with sodium borohydride and boron trifluoride in a solvent to obtain rotigotine of formula (I) or its salt thereof;
optionally liberating the rotigotine free base from the salt obtained in step (i) in the presence of a base and a solvent; and
isolating rotigotine as a free base from the reaction mass obtained in step (ii) or step (i).

Accordingly, in one aspect, the solvent used in step (i) is selected from a group comprising of aromatic solvents, nitrile solvents, ether solvents, N,N-dimethylformamide, and mixtures thereof.

According to still another aspect, the solvent used in step (i) is preferably tetrahydrofuran.

Accordingly, in one aspect, the base used in step (ii) is selected from the group comprising of hydroxides, carbonate salts of alkaline, and alkaline earth metals.

According to still another aspect, the base used in step (ii) is selected from the group comprising of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, calcium carbonate, and cesium carbonate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of rotigotine that is feasible for plant batches, ecofriendly and economically significant.

First embodiment of the present invention is to provide a process for the preparation of rotigotine of formula (I),

comprising the steps of:
reacting compound (S)-1,2,3,4-tetrahydro-5-methoxy-N-propyl-2-naphthalenamine of formula (IV) or its salt thereof

with 2-thienylacetic acid derivative of formula (V) or its salt thereof,

in the presence of a base in a biphasic solvent system to obtain a compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or its salt thereof;

demethylating the compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or its salt thereof obtained in step (i) with aluminium chloride and thiourea in a suitable solvent to obtain a compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (II) or its salt thereof;

treating the compound of formula (II) obtained in step (ii) with sodium borohydride and boron trifluoride in a suitable solvent system to obtain rotigotine of formula (I) or its salt thereof;

optionally liberating the rotigotine free base from the salt obtained in step (iii) in the presence of a suitable base and a solvent; and
isolating rotigotine as a free base from the reaction mass obtained in step (iii) or step (iv).

According to the one embodiment, the “X” in formula (V) in step (i) represents a leaving group. The leaving group is selected from the group comprising of halogens such as chlorine, bromine, or iodine; or alkylsulfonyloxy such as trifluoro methyl sulfonyl oxy; or aryl sulfonyl oxy such as benzene sulfonyl oxy or toluene sulfonyl oxy, preferably the leaving group is chlorine.

According to one embodiment, the biphasic solvent system used in step (i) comprises a mixture of two immiscible solvents, of which one is water and other is a water immiscible organic solvent. The immiscible organic solvent is selected from the group comprising of aliphatic hydrocarbons such as hexane, heptane, cyclohexane, cycloheptane, cyclopentane; or aromatic hydrocarbons such as toluene, or xylene; or halogenated hydrocarbons such as dichloromethane, dichloroethane, or trichloromethane; or esters such as ethyl acetate, methyl acetate, or isopropyl acetate; or ethers such as diethyl ether, diisopropyl ether, or methyl tert-butyl; or its mixtures thereof. Preferably the immiscible organic solvent is dichloromethane.

According to the embodiment the base employed in step (i) is selected from the group comprising hydroxides, carbonate salts of alkaline, alkaline earth metals, and organic bases. Hydroxides or carbonate salts of alkaline, and alkaline earth metal base include, but not limited to, lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, and cesium carbonate; organic bases include, but not limited to, diisopropyl amine, triethyl amine, and diisopropyl ethyl amine. Preferably, the base employed in step (i) is sodium carbonate.

According to one embodiment, the demethylating reagent in step (ii) is selected from the group comprising two reagents include thiourea, and Lewis acid such as boron tribromide, trimethyl borane, or aluminium chloride. Preferably, the lewis acid is aluminium chloride.

According to one embodiment, the suitable solvents used in step (iii) is preferably selected from the group comprising of aromatic solvents such as toluene; nitrile solvents such as acetonitrile; ether solvents such as 1,2-dimethoxyethane, tetrahydrofuran and 1,4-dioxane; N,N-dimethylformamide; and its mixtures thereof. Preferably the suitable solvents used in step (iii) is tetrahydrofuran.

According to one embodiment, the base used in step (iv) is selected from the group comprising of hydroxides, carbonate salts of alkaline, and alkaline earth metals. Hydroxides or carbonate salts of alkaline or alkaline earth metals base include, but not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate sodium hydrogen carbonate, calcium carbonate, and cesium carbonate. Preferably the base is sodium bicarbonate.

Surprisingly, the inventors of the present invention found that the step of compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (II) or its salt thereof treat with sodium borohydride and boron trifluoride to obtain rotigotine compound of formula (I) or its salt thereof, is advantageous than the borane dimethyl sulfide during the reduction of formula (II) since the following:
avoids boron dimethyl sulfide, that is flammable and readily reacts with water to produce flammable gas;
reduces the degradation of the intermediate (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide to (S)-1,2,3,4-tetrahydro-5-hydroxy-N-propyl-2-naphthalenamine during the preparation of rotigotine;
improves yield of the reaction during the preparation of rotigotine;
significantly reduces cost during the preparation of rotigotine; and
avoids the risk for the formation of nitroso amine impurity from boron dimethyl sulfide during the preparation of rotigotine.

Second embodiment of the present invention is to provide a process for the preparation of rotigotine of formula (I),

comprising the step of:
treating compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (II) or its salt thereof;

with sodium borohydride and boron trifluoride in a suitable solvent system to obtain rotigotine of formula (I) or its salt thereof;
optionally liberating the rotigotine free base from the salt obtained in step (i) in the presence of a suitable base and a solvent;
isolating rotigotine as a free base from the reaction mass obtained in step (ii) or step (i).

According to second embodiment, the suitable solvents used in step (i) is selected from the group comprising of aromatic solvents such as toluene; nitrile solvents such as acetonitrile; ether solvents such as 1,2-dimethoxyethane, tetrahydrofuran and 1,4-dioxane; N,N-dimethylformamide; and mixtures thereof, preferably the solvent used in step (i) is tetrahydrofuran.

According to second embodiment, the base used in step (ii) is selected from the group comprising of hydroxides, carbonate salts of alkaline, and alkaline earth metals. Hydroxides or carbonate salts of alkaline or alkaline earth metals base include, but not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, calcium carbonate, cesium carbonate. Preferably, the base used in step (ii) is sodium bicarbonate.

Certain specific aspect and embodiment of the present invention will be explained in detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES

Example-1: Preparation of (S)-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-2-(thiophen-2-yl) acetamide of formula III.
A mixture of (S)-1,2,3,4-tetrahydro-5-methoxy-N-propyl-2-naphthalenamine hydrochloride of formula-IV (10 g), aqueous sodium carbonate solution (16.57 g of sodium carbonate in 100 ml of water) and dichloromethane (80 ml) was maintained for 1 hour at a temperature of 27°C. Then dichloromethane solution of 2-thiophene acetyl chloride (6.9 g of 2-thiophene acetyl chloride in 60 ml of dichloromethane) was slowly added to the reaction mixture at a temperature of 27°C and maintained for 1 hour at a temperature of 27°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the organic layer of the reaction mass was separated. The separated organic layer was washed with water (50 ml); and concentrated under reduced pressure to obtain a residue. % Yield: 94%. Purity by HPLC: 99.47%

Example-2: Preparation of the compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula II:
To a mixture of thiourea (8.9 g), aluminium chloride (15.6 g) and toluene (80 ml) at a temperature of 30±5°C, a toluene solution of residue obtained in example 1 (10 g, of residue dissolved in 50ml of toluene) was slowly added to the mixture at a temperature of 35±5°C. The reaction mixture was heated at the temperature of 65±5°C and maintained for 8 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled at the temperature of 15±5°C; quenched with chilled water (60 ml), and toluene (25 ml), to form a biphasic mixture. The biphasic mixture was stirred for 1 hour at a temperature of 25±5°C. The organic layer was separated and washed with water (50 ml). The washed organic layer was mixed with 1M potassium hydroxide solution at a temperature of 20±5°C, to form a biphasic mixture. The aqueous layer was separated from the biphasic mixture. The pH of the aqueous layer was adjusted to 3.5-4.0 by using concentrated hydrochloric acid at a temperature of 20±5°C. To the aqueous layer toluene was added at a temperature of 25±5°C, to form a biphasic mixture and stirred for 20 minutes. The organic layer was separated and washed with water. The washed organic layer was heated at a temperature 40±5°C. Then n-heptane was slowly added to the heated organic layer at a temperature of 40±5°C. The content was slowly heated at a temperature of 60°C and stirred for 1 hour at a temperature of 60±5°C. The heated contents were cooled at a temperature of 25±5°C and stirred for 30 minutes. The resultant solid was filtered, washed with n-heptane, and dried. % Yield: 61%. Purity by HPLC: 99.80%

Example-3: Preparation of Rotigotine Hydrochloride salt:
To a mixture of solid obtained in Example 2 (10g) and tetrahydrofuran (50 ml), sodium borohydride (2.29 g) was added at a temperature of 5±5°C, followed by the slow addition 45% solution of boron trifluoride in tetrahydrofuran (8.49 g) at a temperature of 5±5°C. The reaction mixture was heated at a temperature of 68±2°C and maintained for 3 hours at a temperature of 68±2°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled at a temperature of 5±5°C, and slowly quenched with concentrated hydrochloric acid (3.75 ml) at a temperature of 10±5°C. The contents were heated at a temperature of 55±5°C and maintained for 3 hours at a temperature of 55±5°C. The heated contents were cooled at a temperature of 25±5°C and charged with water (25ml), followed by slow addition of 10% sodium bicarbonate solution (12 g of sodium bicarbonate in 120 ml of water) and dichloromethane (80ml) to form a bibasic mixture. The organic layer was separated and washed with water (50 ml). The concentrated hydrochloric acid (1.25 ml) was added to the washed organic layer at a temperature of 15±5°C and stirred for 30 minutes. The resultant solid was filtered, washed with dichloromethane (10ml) and dried. % Yield 80%. Purity by HPLC: 99.66%

Example-4: Preparation of Rotigotine:
To a mixture of solid obtained in example 3 (10 g) and ethyl acetate (80 ml), a solution of 10% sodium bicarbonate (5 g of sodium bicarbonate in 50 ml of water) was added at a temperature of 30±5°C and stirred for 20 minutes to form a biphasic mixture. The organic layer was separated and washed with water (50ml). The washed organic layer was concentrated under reduced pressure to obtain a residue. The concentrated residue was mixed with n-heptane (50 ml) at a temperature of 30±5°C; heated a temperature of 55±5°C and maintained for 1 hour at a temperature of 55±5°C. The heated contents were cooled at a temperature of 30±5°C and stirred for 6 hours. The resultant solid was filtered, washed with n-heptane (10ml) and dried. % Yield: 61 %; Purity by HPLC: 99.83%.
,CLAIMS:

1. A process for the preparation of rotigotine of formula (I),

comprising the steps of:
(i) reacting compound (S)-1,2,3,4-tetrahydro-5-methoxy-N-propyl-2-naphthalenamine of formula (IV) or its salt thereof

with 2-thienylacetic acid derivative of formula (V) or its salt thereof,

wherein X represent a leaving group, in presence of a base in a biphasic solvent system to obtain a compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or its salt thereof;

(ii) demethylating the compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or its salt thereof obtained in step (i) with aluminium chloride and thiourea in a solvent to obtain a compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (II) or its salt thereof;

(iii) treating the compound of formula (II) obtained in step (ii) with sodium borohydride and boron trifluoride in a solvent to obtain rotigotine of formula (I) or its salt thereof;

(iv) optionally liberating the rotigotine free base from the salt obtained in step (iii) in the presence of a base and a solvent; and
(v) isolating rotigotine as a free base from the reaction mass obtained in step (iii) or step (iv).

2. The process as claimed in claim 1, wherein the leaving group is selected from the group comprising of halogens include chlorine, bromine, or iodine, alkylsulfonyloxy, trifluoro methyl sulfonyl oxy, and aryl sulfonyl oxy include benzene sulfonyl oxy and toluene sulfonyl oxy.

3. The process as claimed in claim 1, wherein the biphasic solvent system used in step (i) comprises a mixture of water and an immiscible organic solvent.

4. The process as claimed in claim 3, wherein the immiscible organic solvent is selected from the group comprising of aliphatic hydrocarbons include hexane, heptane, cyclohexane, cycloheptane, cyclopentane, aromatic hydrocarbons include toluene, xylene, halogenated hydrocarbons include dichloromethane, dichloroethane, trichloromethane, esters include ethyl acetate, methyl acetate, isopropyl acetate, and ethers include diethyl ether, diisopropyl ether, methyl tert-butyl, and mixtures thereof.

5. The process as claimed in claim 3, wherein the immiscible organic solvent is dichloromethane.

6. The process as claimed in claim 1, wherein the base used in step (i) is selected from the group comprising of hydroxides, carbonate salts of alkali, alkaline earth metals, and organic bases.

7. The process as claimed in claim 1, wherein the base used in step (i) and step (iv) is selected from the group comprising of lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, and cesium carbonate.

8. The process as claimed in claim 1, wherein the solvent used in step (iii) is selected from a group comprising of aromatic solvents, nitrile solvents, ether solvents, N,N-dimethylformamide, and mixtures thereof.

9. The process as claimed in claim 1, wherein the solvent used in step (iii) is tetrahydrofuran.

10. The process as claimed in claim 1, wherein the base used in step (iv) is selected from the group comprising of hydroxides, carbonate salts of alkaline, and alkaline earth metals.

11. A process for the preparation of rotigotine of formula (I),

comprising the step of:

(i) treating compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (II) or its salt thereof;

with sodium borohydride and boron trifluoride in a solvent to obtain rotigotine of formula (I) or its salt thereof;
(ii) optionally liberating the rotigotine free base from the salt obtained in step (i) in the presence of a base and a solvent; and
(iii) isolating rotigotine as a free base from the reaction mass obtained in step (ii) or step (i).

12. The process as claimed in claim 11, wherein the solvent used in step (i) is selected from a group consisting of aromatic solvents, nitrile solvents, ether solvents, N,N-dimethylformamide, and mixtures thereof.

13. The process as claimed in claim 11, wherein the solvent used in step (i) is tetrahydrofuran.

14. The process as claimed in claim 11, wherein the base used in step (ii) is selected from the group comprising of hydroxides, carbonate salts of alkaline, and alkaline earth metals.

15. The process as claimed in claim 11, wherein the base used in step (ii) is selected from the group comprising of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, calcium carbonate, and cesium carbonate.