DESC:RELATED PATENT APPLICATION
This application claims the priority to and benefit of Indian Provisional Patent Application No. 202241001579 filed on January 11, 2022; 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 and of intermediates thereof, which is cost effective and 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, 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 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 to -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 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 preparation of Rotigotine involving 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 (S)-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) demethylation of 2-N-propyl-5-methoxy tetraline by the treatment with 48% hydrobromic acid to obtain 2-N-propyl-5-hydroxy tetraline base; and (ii) the reaction of 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 presence of 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 10,611,749 discloses the process of rotigotine or its salts preparation thereof: the rotigotine process scheme as given below,

reduction of the compound obtains 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 and has an unpleasant smell.

The same Patent discloses the purification of the compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide obtained in step (ii) in n-hexane. The resultant residue in gummy or partially solid in nature. The gummy or partially solid intermediate during the process for Rotigotine is not preferable to handle in large scale operations.

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 improving the preparation of rotigotine and of intermediates thereof, which is cost effective and economically significant.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of Rotigotine and its intermediates thereof.

Another main objective of the present invention is to provide an improved process for the Rotigotine and its intermediates.

Another objective of the present invention is to provide a commercially viable process to prepare the Rotigotine and its intermediates for large scale preparations.

SUMMARY OF THE PRESENT INVENTION

Accordingly, in one aspect of the present invention provides an improved process for the preparation of Rotigotine of formula (I), comprising the step of:

(i) reacting compound (S)-1,2,3,4-tetrahydro-5-methoxy-N-propyl-2- naphthalenamine of formula (IV) or of salts thereof

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

in presence of base to obtain a compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or of salts thereof;

(ii) demethylating the compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or of salts thereof obtained in step (i) with aluminium chloride and thiourea to obtain a compound (2S)-N-(5- hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-ylacetamide of formula (II) or of salts thereof;

(iii) purifying the compound of formula (II) obtained in step (ii) using aliphatic esters such as methyl acetate, methyl ester, ethyl ester or C1-C6 ester, ethyl acetate, and C1-C7 aliphatic hydrocarbons, preferably n-hexane, propyl acetate, butyl acetate, n-butyl acetate, and mixtures thereof;

(iv) reducing the compound of formula (II) obtained in step (iii) with a suitable reducing agent in a solvent to obtain Rotigotine of formula (I) or of salts thereof;

(v) optionally liberating the Rotigotine free base from the salt obtained in step (iv) in presence of suitable base and solvent; and

(vi) isolating Rotigotine as a free base from the reaction mass obtained in step (iv) or step (v).

In some embodiment of the invention, in the above-described process for the preparation of Rotigotine, the said leaving group X is selected from the group comprising of halogen such as chlorine, bromine or iodine; alkylsulfonyloxy such as trifluoromethylsulfonyloxy; or arylsulfonyloxy such as benzenesulfonyloxy.

In some embodiment of the invention, in the above-described process for the preparation of Rotigotine, the base is selected from the group comprising of hydroxide or carbonate salt of alkali or alkaline earth metals. In some embodiment, the base is selected from the group comprising of lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate or cesium carbonate.

In some other embodiment of the invention, in the above-described process for the preparation of Rotigotine, the base is selected from the group comprising of organic bases.

According to one embodiment, the aliphatic ester is ethyl acetate.

According to one embodiment, the solvent is selected from the group comprising hydrocarbons, halogenated hydrocarbons, and mixtures thereof.

In some other embodiment of the invention, the solvent is selected from the group comprising toluene, xylene, hexane, heptane, cyclohexane, dichloromethane, dichloroethane, trichloromethane, monochlorobenzene, ethyl acetate, methyl acetate, propyl acetate, diethyl ether, diisopropyl ether, and mixtures thereof.

According to one embodiment, the reducing agent is selected from the group comprising lithium aluminium hydride (LiAlH4), sodium borohydride (NaBH4), diisobutylaluminium hydride (DIBAL-H), diborane (B2H6), borane dimethyl sulphide ((CH3)2S-BH3), trimethylamine borane ((CH3)3N-BH3), borane-THF complex (BH3OC4H8), and thereof.

According to one embodiment, the purification of the compound of formula-II is done by a process, comprising the steps of:
(a) providing a residue dissolving in aliphatic esters;

(b) heating the solution obtained in step (a) at a temperature between 40°C -50°C;

(c) adding hydrocarbon as antisolvent to the heated solution obtained in step (b);

(d) heating the solution obtained in step (c) at a temperature between 60°C -65°C;

(e) cooling the heated solution obtained in step (d) at a temperature between 20°C -30°C, thereby obtaining a solid compound of formula-II; and

(f) isolating the solid compound of formula-II from a cooled solution obtained in step (e).

According to one embodiment, the hydrocarbons are selected from the group comprising aliphatic hydrocarbons, hexane, n-hexane, heptane, n-heptane, and mixtures thereof.

Another aspect of the present invention provides a process for the preparation of compound of formula (II), comprising the steps of:

(i) reacting compound (S)-1,2,3,4-tetrahydro-5-methoxy-N-propyl-2- naphthalenamine of formula (IV) or of salts thereof

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

in presence of base to obtain a compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or of salts thereof;

(ii) demethylating the compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or of salts thereof obtained in step (i) with aluminium chloride and thiourea to obtain a compound (2S)-N-(5- hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-ylacetamide of formula (II) or of salts thereof; and

(iii) purifying the compound of formula (II) obtained in step (ii) using aliphatic esters such as methyl acetate, methyl ester, ethyl ester or C3-C6 esters, ethyl acetate, and C1-C7 aliphatic hydrocarbons, preferably n-hexane, propyl acetate, butyl acetate, n-butyl acetate, and mixtures thereof.

According to the embodiment of the invention, in the above-described process for the preparation of Rotigotine, the said leaving group X is selected from the group comprising of halogen such as chlorine, bromine or iodine; alkylsulfonyloxy such as trifluoromethylsulfonyloxy; or arylsulfonyloxy such as benzenesulfonyloxy.

According to the embodiment of the invention, in the above-described process for the preparation of Rotigotine, the base is selected from the group comprising of hydroxide, carbonate salts of alkali, and alkaline earth metals. In some embodiment, the base is selected from the group comprising of lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, and calcium carbonate or cesium carbonate.

DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, the present invention describes a process for the preparation of Rotigotine, more particularly, an improved process for the preparation and purification of Rotigotine and its intermediates thereof.

The process is commercially preferable for large scale of preparation of Rotigotine and its intermediates. The improved process is simple and easy in handling large quantities during the preparation of Rotigotine.

One embodiment of the present invention is to provide 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,

in presence of base to obtain a compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-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-naphthalen2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or its salt thereof obtained in step (i) with aluminium chloride and thiourea to obtain a compound (2S)-N-(5- hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-ylacetamide of formula (II) or its salt thereof;

(iii) purifying the compound of formula (II) obtained in step (ii) using aliphatic esters such as methyl acetate, methyl ester, ethyl ester or C1-C6 ester, ethyl acetate, and C5-C7 aliphatic hydrocarbons, preferably n-hexane, propyl acetate, butyl acetate, n-butyl acetate, and mixtures thereof;

(iv) reducing the compound of formula (II) obtained in step (iii) with a suitable reducing agent in a solvent to obtain Rotigotine of formula (I) or its salt thereof;

(v) optionally liberating the Rotigotine free base from the salt obtained in step (iv) in presence of suitable base and solvent; and

(vi) isolating Rotigotine as a free base from the reaction mass obtained in step (iv) or step (v).

Step (i): According to the process of the present invention, the said “X” in compound of formula (V) as mentioned in step (i) represents a leaving group. Preferred leaving group is halogen such as chlorine, bromine and iodine; alkylsulfonyloxy such as trifluoromethylsulfonyloxy; or arylsulfonyloxy such as benzenesulfonyloxy.

According to the process of the present invention, the base employs in the step (i) of the above-described process for the preparation of Rotigotine is selected from the group comprising, but not limited to, hydroxide, carbonate salts of alkali, alkaline earth metals, and organic bases. Preferred base could be selected form a group comprising lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, cesium carbonate, and the like. More preferably, carbonate of sodium or potassium and most preferably, sodium carbonate.

According to the process of the present invention in the step (i) employs a biphasic solvent system comprising 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; and mixtures thereof. Preferably, the immiscible organic solvent is dichloromethane.

Step-(ii): According to the process of the present invention, the demethylating reagent employs in step (ii) is comprising of two reagent which one is thiourea, and another one is Lewis acid such as boron tribromide, trimethyl borane, or aluminium chloride. Preferably the lewis acid is aluminium chloride.

According to the process of the present invention, the solvent employs in step (ii) of the process for the preparation of Rotigotine is selected from the group including, but not limited to, a class of hydrocarbons, halogenated hydrocarbons, and mixtures thereof. Preferably, the solvent is selected from the group comprising toluene, xylene, hexane, heptane, cyclohexane, dichloromethane, dichloroethane, trichloromethane, monochlorobenzene, and the mixtures thereof, most preferably, toluene.

Step (iii): According to the process of the present invention, the purification of formula (II) in step (iii) employs purification techniques such as crystallization, slurry washing, precipitation, distillation or its mixtures thereof. Preferably, the purification of formula (II) in step (iii) employs crystallization, decantation, and most preferably, crystallization.

According to the process of the present invention, the purification of formula (II) employs the mixture of solvents is aliphatic esters such as C1-C6 carbons chain or hydrocarbons contain C5-C7 carbons chain or its mixture thereof. Alternatively, the aliphatic ester is selected from the group comprising methyl acetate, ethyl acetate, propyl acetate, butyl acetate, n-butyl acetate or its mixture thereof. According to one embodiment, the hydrocarbons selected from the group comprising such as pentane, hexane, n-hexane, heptane, n-heptane, and its mixtures thereof. Preferably, the aliphatic ester is selected from the group comprising methyl acetate, ethyl acetate, n-butyl acetate, hexane, n-hexane, heptane, most preferably, ethyl acetate and n-hexane.

Preferably the crystallization of the compound of formula-II is done by a process, comprising the steps of:

(a) providing a residue dissolving in aliphatic esters;

(b) heating the solution obtained in step (a) at a temperature between 40°C -50°C;

(c) adding the hydrocarbon as antisolvent to the heated solution obtained in step (b);

(d) heating the solution obtained in step (c) at a temperature between 60°C -65°C;

(e) cooling the heated solution obtained in step (d) at a temperature between 20°C -30°C, thereby obtaining a solid compound of formula-II; and

(f) isolating the solid compound of formula-II from a cooled solution obtained in step (e).

Step (a): According to the process of the present invention, the residue in step (a) is obtained from the chemical techniques such as evaporation, distillation, vacuum distillation and filtration. Most preferably, the residue in step (a) is obtained by using the distillation technique.

Step (b): According to the process of the present invention, an aliphatic ester such as methyl acetate, ethyl acetate, propyl acetate and butyl acetate or its mixture thereof employs in step (b). Most preferably, the aliphatic ester is ethyl acetate.

Step (c): According to the process of the present invention, hydrocarbons as an antisolvent such as aliphatic hydrocarbons or its mixtures thereof employ in step (b). Preferably, the hydrocarbons are selected from the group comprising red hexane, n-hexane, heptane and n-heptane, and its mixture thereof. Most preferably, the hydrocarbon is n-hexane.

Step (f): According to the process of the present invention, the solid compound of formula-II in step (f) employs isolating techniques such as filtration, vacuum filtration, hot filtration, decantation, precipitation, crystallization, fractional distillation, salting-out. Most preferably, the vacuum filtration technique could be used in step (f). Preferably, the isolated solid in step (f) is crystalline.

Step (iv): According to the process of the present invention, the reducing agent in step (iv) employs Lewis acid, which is boron trifluoride and catalytic hydrogenation. The Lewis acid is selected from the group including, but not limited to, lithium aluminium hydride (LiAlH4), sodium borohydride (NaBH4), diisobutylaluminium hydride (DIBAL-H), diborane (B2H6), borane dimethyl sulphide ((CH3)2S-BH3), trimethylamine borane ((CH3)3N-BH3), borane-THF complex (BH3OC4H8), and the likes. Preferably, alkali metal hydride, most preferably, sodium borohydride (NaBH4) is used in step (iv).

According to the process of the present invention, the Rotigotine obtained in step (iv) is converted into a suitable salt for better isolation and purification of Rotigotine of formula (I). Preferably, Rotigotine of formula (I) is isolated as salt after completion of the reduction of compound of formula (II). Preferably, the salt obtained in step (iv) is converted into a free base comprising the steps of providing a solution of salt of Rotigotine of formula (I) in a biphasic solvent system in presence of base and separating the organic solvent layer containing Rotigotine free base.

Step-(v): According to the process of the present invention, the base employs in step (iv) is selected from the group comprising of hydroxide, carbonate salts of alkaline, and alkaline earth metals. Hydroxide or carbonate salts of alkaline or alkaline earth metal base including, 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 is sodium bicarbonate.

According to the process of the present invention, the biphasic solvent system in the preparation of Rotigotine free base from Rotigotine hydrochloride comprises a mixture of two immiscible solvents, of which one is water and other is a water immiscible organic solvent. The immiscible organic solvent includes, but not limited to, a class of hydrocarbons, halogenated hydrocarbons, esters, ethers, etc. Preferably, employable immiscible organic solvents comprise of a group selected from toluene, xylene, hexane, heptane, cyclohexane, dichloromethane, dichloroethane, trichloromethane, ethyl acetate, methyl acetate, propyl acetate, diethyl ether, diisopropyl ether, and the likes, more preferably, ester and most preferably, ethyl acetate.

According to the process of the present invention, the suitable base employed in step (iv) of the process for the preparation of Rotigotine is selected from the group including, but not limited to, hydroxide, carbonate salts of alkali, and alkaline earth metals. More preferably, the base is carbonate of sodium or potassium.

Another embodiment of the present invention provides a process for the preparation of the compound of formula (II), 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,

in presence of base to obtain a compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-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-naphthalen2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or its salt thereof obtained in step (i) with aluminium chloride and thiourea to obtain a compound (2S)-N-(5- hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-ylacetamide of formula (II) or its salt thereof; and

(iii) purifying the compound of formula (II) obtained in step (ii) using aliphatic esters such as methyl acetate, methyl ester, ethyl ester or C3-C6 esters, ethyl acetate, and C1-C7 aliphatic hydrocarbons preferably n-hexane, propyl acetate, butyl acetate, n-butyl acetate, and its mixture thereof.

Step (i): According to the process of the present invention, the said “X” in compound of formula (V) as mentioned in step (i) represents a leaving group. Preferred leaving group is halogen such as chlorine, bromine and iodine; alkylsulfonyloxy such as trifluoromethylsulfonyloxy; or arylsulfonyloxy such as benzenesulfonyloxy.

According to the process of the present invention, the base used in the step (i) of the above described process for the preparation of Rotigotine is selected from the group comprising, but not limited to, hydroxide, carbonate salts of alkali, alkaline earth metals, and organic bases. Preferably, the base is selected form a group comprising lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, cesium carbonate and the like. More preferably, the base is carbonate of sodium or potassium and most preferably, sodium carbonate.

According to the process of the present invention, the step (i) employs a biphasic solvent system comprising 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 mixture thereof. Preferably, the immiscible organic solvent is dichloromethane.

Step-(ii): According to the process of the present invention, the demethylating reagent in step (ii) is selected from the group comprising the two reagent which one is thiourea, and another one is Lewis acid such as boron tribromide, trimethyl borane, or aluminium chloride. Preferably, the Lewis acid is aluminium chloride.

According to the process of the present invention, the solvent employed in step (ii) of the process for the preparation of Rotigotine is selected from the group including, but not limited to, a class of hydrocarbons, halogenated hydrocarbons, and mixtures thereof. Preferably, the solvent is selected from the group comprising toluene, xylene, hexane, heptane, cyclohexane, dichloromethane, dichloroethane, trichloromethane, monochlorobenzene, and the mixtures thereof, most preferably, toluene.

Step (iii): According to the process of the present invention, the purification of formula (II) employs purification techniques such as crystallization, decantation, slurry washing, precipitation, distillation or its mixture thereof. Preferably, the purification of formula (II) employs crystallization, decantation, and most preferably, crystallization.

Preferably the crystallization of the compound of formula-II is done by a process, comprising the steps of:

(a) providing a residue dissolving in aliphatic esters;

(b) heating the solution obtained in step (a) at a temperature between 40°C -50°C;

(c) adding hydrocarbon as antisolvent to the heated solution obtained in step (b);

(d) heating the solution obtained in step (c) at a temperature between 60°C -65°C;

(e) cooling the heated solution obtained in step (d) at a temperature between 20°C -30°C, thereby obtaining a solid compound of formula-II; and

(f) isolating the solid compound of formula-II from a cooled solution obtained in step (e).

Step (a): According to the process of the present invention, the residue in step (a) is obtained from the chemical techniques such as evaporation, distillation, vacuum distillation and filtration. Most preferably, the residue in step (a) is obtained by using the distillation technique.

Step (b): According to the process of the present invention, an aliphatic ester such as methyl acetate, ethyl acetate, propyl acetate and butyl acetate or its mixture thereof employs in step (b). Most preferably, the aliphatic ester is ethyl acetate.

Step (c): According to the process of the present invention, hydrocarbons as an antisolvent such aliphatic hydrocarbons and its mixtures thereof employ in step (b). Preferably, the hydrocarbons are selected from the group comprising hexane, n-hexane, heptane and n-heptane, and its mixture thereof. Most preferably, the hydrocarbon is n-hexane.

Step (f): According to the process of the present invention, the solid compound of formula-II in step (f) employs isolating techniques such as filtration, vacuum filtration, hot filtration, decantation, precipitation, crystallization, fractional distillation, salting-out. Most preferably, the vacuum filtration technique could be used in step (f). Preferably, the isolated solid in step (f) is crystalline.

Preferably the process of the present invention, an anti-solvent such as aliphatic hydrocarbons employs in step (iii) to obtain crystalline solid.

Preferably, the present invention improves the yield percentage and quality of the compound of formula (II).

Unexpectedly, the inventors of the present invention found that the crude compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-ylacetamide of formula (II) obtained in step (ii) is converted to a solid by the purification techniques using the aliphatic ester as a solvent and aliphatic hydrocarbon as an anti-solvent. The resultant compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-ylacetamide after purification is a solid.

The process of the present invention avoids the gummy or partially solid nature of compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-ylacetamide of formula (II) from the compound of (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl of formula (III) during the preparation process of Rotigotine.

The process of the present invention improves the quality of the solid nature of the compound (2S)-N-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-ylacetamide of formula (II), so that easy to handle and store the compound during large scale preparations.

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 purpose of illustration and should not be constructed 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 (150 g) aqueous sodium carbonate solution (248.5 g of sodium carbonate in 1500 ml of water) and dichloromethane (1200 ml) was maintained for 1 hour at a temperature of 27°C. Then dichloromethane solution of 2-thiophene acetyl chloride in (95.8 g of 2-thiophene acetyl chloride in 750 ml of dichloromethane) was slowly added to the reaction mixture at a temperature of 27°C and maintained for 1 hour at the temperature of 27°C. The progress of the reaction was monitored by HPLC. 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%.

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 (223.2 g), aluminium chloride (223.2 g) and toluene (375 ml) stirred at 0±5°C for 15 minutes. The above mixture temperature was raised at a temperature of 25±5°C and stirred for 60±5 minutes. Then toluene solution compound of formula III obtained in example 1 was slowly added to the mixture at a temperature of 0±5°C. The reaction mixture was heated to 65±5°C and maintained for 8 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to a temperature of 15±5°C; quenched with chilled water (1500 ml), and toluene (750 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 (1050 ml). The washed organic layer was mixed with 2M aqueous potassium hydroxide solution (84 g in 750 ml of water) 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 (750 ml) was added at a temperature of 25±5°C, to form a biphasic mixture and stirred for 20 minutes. The organic layer was concentrated under reduced pressure at a temperature of 55±5°C to obtain a residue. The concentrated residue was dissolved in ethyl acetate (375 ml) and heated to a temperature of 40±5°C. Then n-heptane was slowly added to the heated solution at 40±5°C. Then the content was slowly heated to a temperature of 60°C and stirred for 1 hour at the temperature of 60±5°C. The heated contents were cooled to a temperature of 25±5°C and stirred for 30 minutes. The resultant solid was filtered, washed with n-heptane, and dried. Yield: 68%; purity: 99.3%.

Example 3: Preparation of Rotigotine Hydrochloride salt:

To a mixture of solid obtained in Example 2 (130g) and tetrahydrofuran (780 ml), sodium borohydride (37.1 g) was added at a temperature of 5±5°C, followed by the slow addition 45% solution of boron trifluoride in tetrahydrofuran (241.8 ml) at a temperature of 5±5°C. The reaction mixture was heated to 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 to a temperature of 5±5°C, and slowly quenched with methanol (65 ml) followed by concentrated hydrochloric acid (48.7 ml) at a temperature of 10±5°C. The contents were concentrated at a temperature of 45±5°C to obtain a residue. The concentrated residue was dissolved in dichloromethane (1600 ml) and followed the addition of 10% sodium bicarbonate solution (65 g in 650 ml of water) charged with water (ml), followed by slow addition of 10% sodium bicarbonate solution (12 g of sodium bicarbonate in 120 ml of water) to form a bibasic mixture. The organic layer was separated and washed with water (520 ml). The concentrated hydrochloric acid (56.2 ml) was added to the washed organic layer at a temperature of 5±5°C and stirred for 60 minutes. The resultant solid was filtered, washed with dichloromethane (260 ml) and dried. Yield 80%; purity: 99.74%.

Example 4: Preparation of Rotigotine:
To a mixture of Rotigotine hydrochloride obtained in example 3 (130 g) and ethyl acetate (1040 ml), a solution of 10% sodium bicarbonate (65 g of sodium bicarbonate in 650 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 (130 ml) at a temperature of 30±5°C; heated to a temperature of 55±5°C and maintained for 1 hour at a temperature of 55±5°C. The heated contents were cooled to a temperature of 30±5°C and stirred for 6 hours. The resultant solid was filtered, washed with n-heptane (130ml) and dried. Yield: 57%; Purity: 99.80%. ,CLAIMS:1. A process for the preparation of Rotigotine of formula (I), comprising the step of:

(i) reacting compound (S)-1,2,3,4-tetrahydro-5-methoxy-N-propyl-2- naphthalenamine of formula (IV) or of salts thereof

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

in presence of base to obtain a compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or of salts thereof;

(ii) demethylating the compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or of salts thereof obtained in step (i) with aluminium chloride and thiourea to obtain a compound (2S)-N-(5- hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-ylacetamide of formula (II) or of salts thereof;

(iii) purifying the compound of formula (II) obtained in step (ii) using aliphatic esters;

(iv) reducing the compound of formula (II) obtained in step (iii) with a suitable reducing agent in a solvent to obtain Rotigotine of formula (I) or of salts thereof;

(v) optionally liberating the Rotigotine free base from the salt obtained in step (iv) in presence of suitable base and solvent; and

(vi) isolating Rotigotine as a free base from the reaction mass obtained in step (iv) or step (v).

2. The process as claimed in Claim 1, wherein the base is selected from the group comprising hydroxide, carbonate salts of alkali, alkaline earth metals, and organic bases.

3. The process as claimed in Claim 1, wherein the base is selected from the group comprising lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, and cesium carbonate.

4. The process as claimed in Claim-1, wherein the aliphatic ester is ethyl acetate.

5. The process as claimed in Claim-1, wherein the aliphatic esters are selected from the group comprising methyl acetate, ethyl acetate, methyl ester, ethyl ester or C1-C6 ester, and C1-C7 aliphatic hydrocarbons, propyl acetate, butyl acetate, n-butyl acetate, and mixture thereof.

6. The process as claimed in Claim-5, wherein the aliphatic hydrocarbons are n-hexane.

7. The process as claimed in Claim-1, wherein the solvent is selected from the group comprising hydrocarbons, halogenated hydrocarbons, and mixtures thereof.

8. The process as claimed in Claim-1, wherein the solvent is selected from the group comprising toluene, xylene, hexane, heptane, cyclohexane, dichloromethane, dichloroethane, trichloromethane, monochlorobenzene, ethyl acetate, methyl acetate, propyl acetate, diethyl ether, diisopropyl ether, and mixture thereof.

9. The process as claimed in Claim-1, wherein the reducing agent is selected from the group comprising lithium aluminium hydride (LiAlH4), sodium borohydride (NaBH4), diisobutylaluminium hydride (DIBAL-H), diborane (B2H6), borane dimethyl sulphide ((CH3)2S-BH3), trimethylamine borane ((CH3)3N-BH3), borane-THF complex (BH3OC4H8), and thereof.

10. The process as claimed in Claim-1, wherein the purification of the compound of formula-II is done by a process, comprising the steps of:

(a) providing a residue dissolving in aliphatic esters;

(b) heating the solution obtained in step (a) at a temperature between 40°C -50°C;

(c) adding hydrocarbon as antisolvent to the heated solution obtained in step (b);

(d) heating the solution obtained in step (c) at a temperature between 60°C -65°C;

(e) cooling the heated solution obtained in step (d) at a temperature between 20°C -30°C, thereby obtaining a solid compound of formula-II; and

(f) isolating the solid compound of formula-II from a cooled solution obtained in step (e).

11. The process as claimed in Claim-10, wherein the hydrocarbons are selected from the group comprising aliphatic hydrocarbons, hexane, n-hexane, heptane, n-heptane, and mixtures thereof.

12. A process for the preparation of compound of formula (II), comprising the steps of:

(i) reacting compound (S)-1,2,3,4-tetrahydro-5-methoxy-N-propyl-2- naphthalenamine of formula (IV) or of salts thereof

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

in presence of base to obtain a compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or of salts thereof;

(ii) demethylating the compound (2S)-N-(5-methoxy-1,2,3,4-tetrahydro-naphthalen2-yl)-N-propyl-2-thiophen-2-yl-acetamide of formula (III) or of salts thereof obtained in step (i) with aluminium chloride and thiourea to obtain a compound (2S)-N-(5- hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-2-thiophen-2-ylacetamide of formula (II) or of salts thereof; and

(iii) purifying the compound of formula (II) obtained in step (ii) using aliphatic esters.

13. The process as claimed in Claim 12, wherein the base is selected from the group comprising hydroxide, carbonate salts of alkali, alkaline earth metals, and organic bases.

14. The process as claimed in Claim 12, wherein the base is selected from the group comprising lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, and cesium carbonate.

15. The process as claimed in Claim-12, wherein the aliphatic ester is ethyl acetate.

16. The process as claimed in Claim-12, wherein the aliphatic esters are selected from the group comprising methyl acetate, ethyl acetate, methyl ester, ethyl ester or C1-C6 ester, and C1-C7 aliphatic hydrocarbons, propyl acetate, butyl acetate, n-butyl acetate, and mixture thereof.

17. The process as claimed in Claim-16, wherein the aliphatic hydrocarbons are n-hexane.

18. The process as claimed in Claim-12, wherein the purification of the compound of formula-II is done by a process, comprising the steps of:

(a) providing a residue dissolving in aliphatic esters;

(b) heating the solution obtained in step (a) at a temperature between 40°C -50°C;

(c) adding hydrocarbon as antisolvent to the heated solution obtained in step (b);

(d) heating the solution obtained in step (c) at a temperature between 60°C -65°C;

(e) cooling the heated solution obtained in step (d) at a temperature between 20°C -30°C, thereby obtaining a solid compound of formula-II; and

(f) isolating the solid compound of formula-II from a cooled solution obtained in step (e).

19. The process as claimed in Claim-18, wherein the hydrocarbons are selected from the group comprising aliphatic hydrocarbons, hexane, n-hexane, heptane, n-heptane, and mixtures thereof.