DESC:Title of the Invention
An improved process for the preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine(2R,3R)-2,3-bis(benzoyloxy)succinic acid compound of Formula I.
Field of the Invention
The present invention relates to an improved process for the preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine(2R,3R)-2,3-bis (benzoyloxy) succinic acid compound of Formula I.

Background of the Invention
(S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine(2R,3R)-2,3bis (benzoyloxy) succinic acid compound of Formula I is well known intermediate and especially used in the preparation of Rotigotine.

Rotigotine is chemically known as (6S)-6-{propyl [2-(2-thienyl)ethyl]amino}-5,6,7,8-
tetrahydro-1-naphthalenol

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 process for the preparation of Rotigotine is disclosed in US 4,564,628, US 4,885,308, U.S. Patent No. 8,614,337 and publication Journal of Chemical Society 1970, page no; 1667-74.

The process in the above references required more number of purifications and reported lower yields.

Therefore, it would be desirable and of paramount importance to have an improved process for the preparation of S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine(2R,3R)-2,3 bis(benzoyloxy) succinic acid compound of Formula-I, by employing inexpensive, readily available, easy to handle reagents. It would also be desirable to have a process that can be readily scaled up and which does not require more purification steps, thereby making it more suitable for industrial scale preparation.

Summary of the Invention
The present invention provides an improved process for the preparation of S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine(2R,3R)-2,3 bis(benzoyloxy) succinic acid compound of Formula I.

In one aspect of the present invention is to provide a process for the preparation of
S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine(2R,3R)-2,3 bis (benzoyloxy) succinic acid compound of Formula (I) which comprising;

i) imine formation of compound of Formula II

with 1.5 equivalents of n-propylamine and 0.01 equivalents to 0.1 equivalents of acetic acid in presence of methanol to obtain compound of Formula III;

ii) reduction of compound of Formula III in presence of 0.3 equivalents to 1.0 equivalents of sodium borohydride to obtain the compound of Formula IV;

iii) salt formation of compound of Formula IV with concentrated HCl in presence of tetrahydrofuran to obtain the compound of Formula V;

iv) removal of salt of compound of Formula V in presence of potassium carbonate water and dichloromethane to obtain the compound of Formula VI;

v) resolution of compound of Formula VI in presence of 0.5 equivalents to 2.5 equivalents of dibenzoyl- L-tartaric acid and 25.0 Volumes to 30.0 Volumes of ethanol to obtain compound of Formula I

Detailed Description of the Invention
Accordingly, the present invention relates to an improved process for the preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine(2R,3R)-2,3 bis (benzoyloxy) succinic acid compound of Formula I.

(S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine((2R,3R)-2,3 bis (benzoyloxy) succinic acid compound of Formula I is well known intermediate and especially used in the preparation of Rotigotine.
The main embodiment of the present invention provides an improved process for the preparation of compound of Formula I, which is outlined below in Scheme-:

In stage i), imine formation of compound of Formula II with 1.5 equivalents of n-propylamine and 0.01 equivalents to 0.1 equivalents of acetic acid in presence of methanol to obtain the compound of Formula III;

Acetic acid used in the reaction is ranging from 0.01 equivalents to 0.1 equivalents, preferably 0.05 equivalents. The reaction temperature may range from 0 °C to 20 °C and preferably at a temperature in the range from 0 oC to 10 oC. The duration of the reaction may range from 30 minutes hours to 1 hour, preferably for a period of 30 minutes.

In stage ii), reduction of compound of Formula III in presence of 0.3 equivalents to 1.0 equivalents sodium borohydride to obtain the compound of Formula IV;

Sodium borohydride used in reaction is ranging from 0.3 equivalents to 1.0 equivalents, preferably 0.5 equivalents. The reaction temperature may range from 0 °C to 20 °C and preferably at a temperature in the range from 0 to 10 oC or ambient temperature. The duration of the reaction may range from 2 hours to 5 hours, preferably for a period of 3 hours to 4 hours.

In stage iii), salt formation of compound of Formula IV with concentrated HCl in presence of tetrahydrofuran to obtain the compound of Formula V;

The reaction temperature may range from 40 °C to 70 °C and preferably at a temperature in the range from 50 oC to 60 oC or ambient temperature. The duration of the reaction may range from 2 hours to 5 hours, preferably for a period of 2 hours.

In stage iv), removal of salt of compound of Formula V in presence of 10% to 30% of potassium carbonate, water and dichloromethane to obtain the compound of Formula VI;

Potassium carbonate used in the reaction ranging from 10% to 30%, preferably 20%. The reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25 oC to 35 oC or ambient temperature. The duration of the reaction may range from 30 minutes to 1 hour, preferably for a period of 30 minutes.

In stage v), resolution of compound of Formula VI in presence of 0.5 equivalents to 2.5 equivalents of dibenzoyl- L -tartaric acid and 10 Volumes to 40 Volumes of ethanol to obtain the compound of Formula I

Dibenzoyl- L -tartaric acid used in the reaction ranging from 0.5 equivalents to 2.5 equivalents, preferably 2.25 equivalents. Aqueous ethanol used in the reaction is ranging from 10 Volumes to 40 Volumes, preferably 25.0 Volumes to 30.0 Volumes. The reaction temperature may range from 60 °C to 90 °C and preferably at a temperature in the range from 70 oC to 80 oC or ambient temperature. The duration of the reaction may range from 5 hours to 9 hours, preferably for a period of 6 hours to 8 hours.

EXPERIMENTAL PORTION:

The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

EXAMPLES:
Example-1: Process for the preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine(2R,3R)-2,3 bis(benzoyloxy) succinic acid compound of Formula I.
5-methoxy 2-tetralone (1.0 equivalents) was dissolved in Methanol (5.0 Volumes) and stirred for 10 minutes at 25-30 °C then add n-Propyl amine (1.5 equivalents) and acetic acid (0.05 equivalents) sequentially at ambient temperature. The resulting mixture was stirred for 30 minutes at the same temperature then cooled to 0-10 oC then add sodium borohydride (0.5 equivalents) to the reaction mixture portion wise by maintaining the internal temperature at 0-10 oC. The reaction was stirred for 3-4 hours at ambient temperature then quenched with ice cold water (1.0 Volumes). Then the reaction mixture was distilled under reduced pressure to afford residue which was diluted with MDC (10.0 Volumes) and purified water (5.0 Volumes). Separate the two layers and extracted with MDC (2x5.0 Volumes). The combined organic layer was evaporated under reduced pressure to afford residue which was directly used for hydrochloride salt formation.

The above residue was dissolved in THF (7.0 Volumes) and added concentrated HCl (1.0 Volumes) dropwise at ambient temperature. The reaction was heated to 50-60 oC maintain for 30 minutes, cooled to ambient temperature then stirred for 2 hours. Filter the precipitated solid and washed with THF (4.0 Volumes) to afford hydrochloride salt.

To the above hydrochloride salt add purified water (10.0 Volumes) and adjusted the pH to 9-10 with 20% aqueous potassium carbonate solution and extracted with MDC (2x 10.0 Volumes). The combined organic extracts were washed with water (2x5.0 Volumes) and evaporated under reduced pressure to afford free base as brown liquid which was directly used for L-DBTA salt formation.

To a stirred solution of dibenzoyl L-Tartaric acid (2.5 equivalents based on above free base weight) in 10% aqueous ethanol (4.0 Volumes) was added a solution of free base in 10% aqueous ethanol (6.0 Volumes) at 70-80 oC stirred for 30 minutes at same temperature before gradually cooled to ambient temperature. The reaction was stirred for 6-8 hours then filtered the precipitated solid and washed with ethanol (1.0 Volume) to afford L-DBTA salt as white colour solid which was analysed by chiral HPLC and obtained 99.0:1.0 of diastereomeric ratio.
Yield: 30-35 %.

Example-2:
5-methoxy 2-tetralone (1.0 equivalents) was dissolved in Methanol (5.0 Volumes) and stirred for 10 minutes at 25-30 °C then add n-Propyl amine (1.5 equivalents) and acetic acid (0.05 equivalents) sequentially at ambient temperature. The resulting mixture was stirred for 30 minutes at the same temperature then cooled to 0-10 oC then add sodium borohydride (0.5 equivalents) to the reaction mixture portion wise by maintaining the internal temperature at 0-10 oC. The reaction was stirred for 3-4 hours at ambient temperature then quenched with ice cold water (1.0 Volume). Then the reaction mixture was distilled under reduced pressure to afford residue which was diluted with MDC (10.0 Volumes) and purified water (5.0 Volumes). Separate the two layers and extracted with MDC (2 x5.0 Volumes). The combined organic layer was evaporated under reduced pressure to afford residue which was directly used for hydrochloride salt formation.

The above residue was dissolved in THF (7.0 Volumes) and added concentrated HCl (1.0 Volume) dropwise at ambient temperature. The reaction was heated to 50-60 oC for 30 minutes, cooled to ambient temperature and stirred for 2 hours. Filter the precipitated solid and washed with THF (4.0 Volumes) to afford hydrochloride salt.

To the above hydrochloride salt was add purified water (10.0 Volumes) and adjusted the pH to 9-10 with 20% aqueous potassium carbonate solution and extracted with MDC (2x10.0 Volumes). The combined organic layers extracts were washed with water (2x5.0 Volumes) and evaporated under reduced pressure to afford free base as brown liquid which was directly used for L-DBTA salt formation.

To a stirred solution of dibenzoyl L-Tartaric acid (2.0 equivalents based on above free base weight) in 10% aqueous ethanol (4.0 Volumes) was added a solution of free base in 10% aqueous ethanol (6.0 Volumes) at 70-80oC and stirred for 30 minutes at same temperature before gradually cooled to ambient temperature. The reaction was stirred for 6-8 hours to precipitate solid. Filter the precipitated solid and washed with ethanol (1.0 Volume) to afford L-DBTA salt as white colour solid which was analysed by chiral HPLC and obtained 80:20 of diastereomeric ratio.
Yield: 35-40 %

Example-3:
5-methoxy 2-tetralone (1.0 equivalents) was dissolved in Methanol (5.0 Volumes) and stirred for 10 minutes at 25-30 °C then add n-Propyl amine (1.5 equivalents) and acetic acid (0.05 equivalents) sequentially at ambient temperature. The resulting mixture was stirred for 30 minutes at the same temperature then cooled to 0-10 oC then add sodium borohydride (0.5 equivalents) to the reaction mixture portion wise by maintaining the internal temperature at 0-10 oC. The reaction was stirred for 3-4 hours at ambient temperature then quenched with ice cold water (1.0 Volume). Then the reaction mixture was distilled under reduced pressure to afford residue which was diluted with MDC (10.0 Volumes) and purified water (5.0 Volumes). Separate the two layers and extracted with MDC (2 X 5.0 Volumes). The combined organic layer was evaporated under reduced pressure to afford residue which was directly used for hydrochloride salt formation.

The above residue was dissolved in THF (7.0 Volumes) and added concentrated HCl (1.0 Volume) dropwise at ambient temperature. The reaction mixture was heated to 50-60 oC maintain for 30 minutes then cooled to ambient temperature and stirred for 2 hours. Filter the precipitated solid and washed with THF (4.0 Volumes) to afford hydrochloride salt.
To the above hydrochloride salt add purified water (10.0 Volumes) and adjusted the pH to 9-10 with 20% aqueous potassium carbonate solution and extracted with MDC (2x 10.0 Volumes). The combined organic extracts were washed with water (2x5.0 Volumes) and evaporated under reduced pressure to afford free base as brown liquid which was directly used for L-DBTA salt formation.

To solution of dibenzoyl L-Tartaric acid (1.5 equivalents based on above free base weight) in 10% aqueous ethanol (4.0 Volumes) was added in a solution of free base in 10% aqueous ethanol (6.0 Volumes) in at 70-80 oC and stirred for 30 minutes at same temperature and gradually cooled to ambient temperature. The reaction was stirred for 6-8 hours to precipitate solid. Filter the precipitated solid and washed with ethanol (1.0 Volume) to afford L-DBTA salt as white colour solid which was analysed by chiral HPLC and obtained 75:25 of diastereomeric ratio.
Yield: 40-45 %.

Example : 4
5-Methoxy-2-tetralone (1.0 equivalents) was dissolved in Methanol (5.0 Volumes) and stirred for 10 minutes at 25-30 °C then add n-propyl amine (1.5 equivalents) and acetic acid (0.05 equivalents) sequentially to reaction mass at 25-30 °C. The resulting mixture was stirred for 30 minutes at the same temperature and cooled to 0-10 oC then add sodium borohydride (0.5 equivalents) to the reaction mixture in portion wise by maintaining the internal temperature at 0-10 oC. The reaction was stirred for 3-4 hours at ambient temperature then quenched with ice cold water (1.0 Volume). Then the reaction mixture was distilled under reduced pressure to afford residue which was diluted with MDC (10.0 Volumes) and purified water (5.0 Volumes). Separate the organic layers and extracted with MDC (2x5.0 Volumes). The combined organic layer was evaporated under reduced pressure to afford residue which was directly used for hydrochloride salt formation.

The above residue was dissolved in THF (7.0 Volumes) and added concentrated HCl (1.0 Volume) dropwise to the reaction mixture at ambient temperature. The reaction mixture was heated to 50-60 oC maintain for 30 minutes then cooled to ambient temperature and stirred for 2 hours. Filter the precipitated solid and washed with THF (4.0 Volumes) to afford hydrochloride salt.

To the above hydrochloride salt add purified water (10.0 Volumes) and adjust the pH to 9-10 with 20% aqueous potassium carbonate solution and extracted with MDC (2x10.0 Volumes). The combined organic layers extracts were washed with water (2x5.0 Volumes) and evaporated under reduced pressure to afford free base as brown liquid which was directly used for L-DBTA salt formation.

To a solution of dibenzoyl L-tartaric acid (1.0 equivalents based on above free base weight) in 10% aqueous ethanol (4.0 Volumes) was added in a solution of free in 10% aqueous ethanol (6.0 Volumes) at 70-80 oC, stirred for 30 minutes at same temperature and gradually cooled to ambient temperature. The reaction was stirred for 6-8 hours to precipitate solid. Filter the precipitated solid and washed with ethanol (1.0 Volumes) to afford L-DBTA salt as white colour solid, which was analysed by chiral HPLC and obtained 55:45 of diastereomeric ratio.
Yield: 45-50 %.

Example-5: Recovery of Dibenzoyl L-Tartaric acid.
The Aqueous ethanol mother liquors from example-4 were evaporated under reduced pressure to afford crude compound mixture of dibenzoyl L-Tartaric acid and diastereomeric L-DBTA salt. To this crude add purified water (10.0 Volumes) and adjusted the pH to 9-10 with 20% aqueous NaOH solution and extracted with MDC (2x10.0 Volumes). To the aqueous layer add concentrated HCl (1.0 V) dropwise at ambient temperature, stirred and filtered the solids then washed with water up to pH of mother liquors reaches to 4.0-4.5. Suck dry and dry in vacuum then record the SOR.
SOR: [a]20/D -116°, c = 9 in ethanol.
,CLAIMS:We claim:
1. A process for the preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine(2R,3R)-2,3 bis (benzoyloxy) succinic acid compound of Formula I

which comprises:
i) imine formation of a compound of Formula II

with 1.5 equivalents of n-propylamine and 0.01 equivalents to 0.1 equivalents of acetic acid in the presence of methanol to obtain the compound of Formula III;

ii) reduction of the compound of Formula III in the presence of 0.3 equivalents to 1.0 equivalents of sodium borohydride to obtain the compound of Formula IV;

iii) salt formation of the compound of Formula IV with concentrated HCl in the presence of tetrahydrofuran to obtain the compound of Formula V;

iv) removal of salt of the compound of Formula V in the presence of potassium carbonate water and dichloromethane to obtain the compound of Formula VI;

v) resolution of the compound of Formula VI in the presence of 0.5 equivalents to 2.5 equivalents of dibenzoyl- L-tartaric acid and 25.0 Volumes to 30.0 Volumes of ethanol to obtain the compound of Formula I

2. The process as claimed in claim 1, wherein step (iv) is carried from 10% to 30% of potassium carbonate.