DESC:An improved process for the preparation of Rotigotine using resolving agents.

Field of the Invention
The present invention relates to an improved process for the preparation of Rotigotine by using resolving agents.

Background of the Invention
Rotigotine is chemically known as (6S)-6-{propyl [2-(2-thienyl)ethyl]amino}-5,6,7,8-
tetrahydro-1-naphthalenol is represented by a molecular formula of C19H25NOS, having the formula (I) as mentioned below.

Rotigotine is a new non-ergolinic dopamine agonist. In May 2007, the U.S. FDA approved for the treatment of the signs and symptoms of early-stage idiopathic Parkinson’s disease. Rotigotine is marketed in USA and Europe under the brand name of “NEUPRO” for the adjuvant treatment of early secondary Parkinson’s disease and advanced Parkinson’s disease.

Rotigotine was first disclosed in the US Patent No. 4,564,628 US Patent No 4,657,925 discloses the levo isomer of 2(N-propyl-N-thienylethyl-amino)-5-hydroxytetralin (Rotigotine).

The process for the preparation of Rotigotine is disclosed in US 4,885,308; US 6,372,920; US 8,614,337; WO 2008146284 and publication Journal of Chemical Society 1970, page no: 1667-74.

None of the prior art process disclose the commercial process for the preparation of Rotigotine. Moreover, prior art process involves the use of PtO2 and BBr3 for the preparation of Rotigotine which are hazardous and not amenable for the industrial scale and their synthesis reported in the above references requires more number of purifications and subsequently reported lower yields.

Therefore, it would be desirable and paramount importance to have an improved process for the preparation of Rotigotine with resolving agents, 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 main aspect of the present invention is to provide an improved process for the preparation of Rotigotine with resolving agents.

Another aspect, the present invention is to provide an improved process for the preparation of Rotigotine, which comprising the steps of:
i. reacting 5-methoxy-2-tetralone compound of Formula II

with n-propyl amine in presence of an acid in a solvent to obtain compound of Formula III(a)

Formula III(a) is reacted in-situ with a reducing agent to obtain compound of Formula III(b)

Formula III(b) is reacted in-situ with an acid in a solvent to obtain compound of Formula III(c)

desalination of compound of Formula III(c) in presence of base and solvent to obtain compound of Formula III(d)

treating the compound of Formula III(d) with compound of formula IV to obtain optically active compound of Formula V

Wherein R is selected from

ii. demethylating of compound of Formula V in presence of base in a solvent followed by reacting with hydrobromic acid to obtain compound of Formula VI

iii. reacting the compound of Formula VI with 2-thienylacetic acid in presence of base in a solvent to obtain Rotigotine hydrochloride salt of Formula VII

iv. treating the Rotigotine hydrochloride salt of Formula VII with aqueous ammonia in a solvent to obtain Rotigotine compound of Formula I.

Detailed Description of the Invention

Accordingly, the present invention relates to an improved process for the preparation of Rotigotine by using resolving agents.

Solvents used throughout the invention is selected from the group consisting of hydrocarbon solvents such as pentane, hexane, heptane, xylene or toluene; alcoholic solvent such as methanol, ethanol, propanol or isopropanol; chloro solvents such as dichloromethane, chloroform, ethylene chloride or carbon tetrachloride; polar aprotic solvents such as dimethyl sulfoxide, dimethyl formamide or dichloromethane.

Base used throughout the invention is selected from the group consisting of Sodium cyanoborohydride, Sodium hydride, Sodium borate, Borax Sodium aluminum hydride or Lithium borohydride.

Acids used throughout the invention is selected from the group consisting of pyridine hydrochloride, sulphuric acid, sulphurous acid, nitric acid, nitrous acid, hydrochloric acid, hydrobromic acid, acetic acid, sulfonic acids, phosphoric acids, carboxylic acids, Formic acid or Propionic acid

The schematic description of the process as shown in Scheme I.

In stage i), reacting 5-methoxy-2-tetralone compound of Formula II with n-propylamine in presence of catalytic amount of acetic acid, methanol to obtain imine compound of Formula III(a);

The reaction temperature may range from 20 °C to 25 °C and preferably at a temperature in the range from 20 oC to 25 oC. The duration of the reaction may range from 30 minutes to 1 hour, preferably for a period of 30 minutes.

Reduction of Formula III(a) in presence of reducing agent to obtain the compound of Formula III(b);

The reaction temperature may range from 20 °C to 30 °C and preferably at a temperature in the range from 20 °C to 25 oC. The duration of the reaction may range from 2 hours to 5 hours, preferably for a period of 3 hours to 4 hours.

Salt formation of compound of Formula III(b) in presence of acid in a solvent to obtain the compound of Formula III(c);

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. The duration of the reaction may range from 30 minutes to 2 hours, preferably for a period of 2 hours.

Desalination of compound of Formula III(c) with base in a solvent to obtain the compound of Formula III(d), which is directly treated with compound of Formula IV in a solvent to obtain compound of Formula V;

The reaction temperature may range from 20 °C to 80 °C and preferably at a temperature in the range from 25 oC to 75 oC. The duration of the reaction may range from 30 minutes to 8 hours, preferably for a period of 7 hours.

In stage ii), salt formation of compound of Formula V with hydrobromic acid in presence of base in a solvent to obtain the compound of Formula VI;

The reaction temperature may range from 90 °C to 115 °C and preferably at a temperature in the range from 100 oC to 110 oC. The duration of the reaction may range from 3 to 5 hours, preferably for a period of 4 hours.

In stage iii), condensation of compound of Formula VI with 2-thienylacetic acid in presence of base in a solvent to obtain compound in suit react with HCl to obtain Rotigotine HCl salt of compound of Formula VII;

The reaction temperature may range from 90 °C to 115 °C and preferably at a temperature in the range from 100 oC to 110 oC. The duration of the reaction may range from 3 to 5 hours, preferably for a period of 4 hours.

In stage iv), desalination of compound of Formula VII with base in a solvent to obtain Rotigotine compound of Formula I.

The reaction temperature may range from 20 °C to 35 °C and preferably at a temperature in the range from 25 oC to 30 oC. The duration of the reaction may range from 3 to 4 hours, preferably for a period of 2 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
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) portion wise to the reaction mixture 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 dichloromethane (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 tetrahydrofuran (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 min, 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 salt formation.

Example-2: Preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(3,5-dimethoxybenzamido)-2-phenylacetic acid.
(R)-2-(3,5-dimethoxybenzamido)-2-phenylacetic acid (0.55 equivalents based on above free base weight) was dissolved in a mixture of acetonitrile-water (6:4, 4.0 Volumes) was added to a mixture of acetonitrile-water (6:4, 6.0 Volumes) solution obtained in example 1 at 25-30 oC. Then heated to 70-80 oC and maintained for 30 minutes at same temperature, gradually cooled to ambient temperature. After maintain the reaction at ambient temperature for 6-8 hours the solid precipitate was observed. Filtered the precipitated solid and washed with acetonitrile (1.0 Volume) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(3,5-dimethoxybenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 80:20 (80% (S)-Isomer, 20% (R)-Isomer) of diastereomeric ratio, which was recrystallized successively three times in acetonitrile-water mixture (8:2, 5.0 Volumes) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(3,5-dimethoxybenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 99:1 (99.0% (S)-Isomer, 1.0% (R)-Isomer )of diastereomeric ratio.
Yield: 25-30 %.

Example-3: Preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(3,5-dichlorobenzamido)-2-phenylacetic acid.
(R)-2-(3,5-dichlorobenzamido)-2-phenylacetic acid (0.55 equivalents based on above free base weight) was dissolved in a mixture of acetonitrile-water (6:4, 4.0 Volumes) was added to a mixture of acetonitrile-water (6:4, 6.0 Volumes) solution obtained in example 1 at 25-30 oC. Then heated to 70-80 oC maintained for 30 minutes at same temperature, gradually cooled to ambient temperature and maintained for 6-8 hours to precipitate solid. Filtered the precipitated solid and washed with acetonitrile (1.0 Volume) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(3,5-dichlorobenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 80:20 (80% (S)-Isomer, 20% (R)-Isomer) of diastereomeric ratio, which was recrystallized successively three times in acetonitrile-water mixture (8:2, 5.0 V) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(3,5-dichlorobenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 99.2:0.8 (99.2% (S)-Isomer, 0.8% (R)-Isomer )of diastereomeric ratio.
Yield: 27-32 %.

Example-4: Preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(4-nitrobenzamido)-2-phenylacetic acid.
(R)-2-(4-nitrobenzamido)-2-phenylacetic acid (0.55 equivalents based on above free base weight) was dissolved in a mixture of acetonitrile-water (6:4, 4.0 Volumes) was added to a mixture of acetonitrile-water (6:4, 6.0 Volumes) solution obtained in example 1 at 25-30 oC. Then heated to 70-80 oC maintained for 30 minutes at same temperature, gradually cooled to ambient temperature and maintained for 6-8 hours to precipitate solid. Filtered the precipitated solid and washed with acetonitrile (1.0 Volume) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(4-nitrobenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 78:22 (78% (S)-Isomer, 22% (R)-Isomer) of diastereomeric ratio, which was recrystallized successively three times in acetonitrile-water mixture (8:2, 5.0 V) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(4-nitrobenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 99:1 (99.0% (S)-Isomer, 1.0% (R)-Isomer )of diastereomeric ratio.
Yield: 25-28 %.

Example-5: Preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(4-nitrobenzamido)-2-phenylacetic acid.
(R)-2-(2-nitrobenzamido)-2-phenylacetic acid (0.55 equivalents based on above free base weight) was dissolved in a mixture of acetonitrile-water (6:4, 4.0 Volumes) was added to a mixture of acetonitrile-water (6:4, 6.0 Volumes) solution obtained in example 1 at 25-30 oC. Then heated to 70-80 oC maintained for 30 minutes at same temperature, gradually cooled to ambient temperature and maintained for 6-8 hours to precipitate solid. Filtered the precipitated solid and washed with acetonitrile (1.0 Volume) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(2-nitrobenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 75:25 (75% (S)-Isomer, 25% (R)-Isomer) of diastereomeric ratio, which was recrystallized successively three times in acetonitrile-water mixture (8:2, 5.0 V) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(2-nitrobenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 98.7:1.3 (98.7% (S)-Isomer, 1.3% (R)-Isomer )of diastereomeric ratio.
Yield: 25-28 %.

Example-6: Preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(2-hydroxybenzamido)-2-phenylacetic acid.
(R)-2-(2-hydroxybenzamido)-2-phenylacetic acid (0.55 equivalents based on above free base weight) was dissolved in a mixture of acetonitrile-water (6:4, 4.0 Volumes) was added to a mixture of acetonitrile-water (6:4, 6.0 Volumes) solution obtained in example 1 at 25-30 oC. Then heated to 70-80 oC maintained for 30 minutes at same temperature, gradually cooled to ambient temperature and maintained for 6-8 hours to precipitate solid. Filtered the precipitated solid and washed with acetonitrile (1.0 Volume) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(2-hydroxybenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 72:28 (72% (S)-Isomer, 28% (R)-Isomer) of diastereomeric ratio, which was recrystallized successively three times in acetonitrile-water mixture (8:2, 5.0 V) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(2-hydroxybenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 98.7:1.3 (98.7% (S)-Isomer, 1.3% (R)-Isomer )of diastereomeric ratio.
Yield: 22-25 %.

Example-7: Preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(2-aminobenzamido)-2-phenylacetic acid.
(R)-2-(2-aminobenzamido)-2-phenylacetic acid (0.55 equivalents based on above free base weight) was dissolved in a mixture of acetonitrile-water (6:4, 4.0 Volumes) was added to a mixture of acetonitrile-water (6:4, 6.0 Volumes) solution of above free base at 25-30 oC. Then heated to 70-80 oC maintained for 30 minutes at same temperature, gradually cooled to ambient temperature and maintained for 6-8 hours to precipitate solid. Filtered the precipitated solid and washed with acetonitrile (1.0 Volume) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(2-aminobenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 72:28 (72% (S)-Isomer, 28% (R)-Isomer) of diastereomeric ratio, which was recrystallized successively three times in acetonitrile-water mixture (8:2, 5.0 V) to afford (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (R)-2-(2-aminobenzamido)-2-phenylacetic acid which was analysed by chiral HPLC and obtained 98.7:1.3 (98.7% (S)-Isomer, 1.3% (R)-Isomer )of diastereomeric ratio.
Yield: 21-25 %.

Example-8: Process for the preparation of (S)-6-(Propylamino)-5,6,7,8-tetrahydronaphthalen-1-ol hydrobromide salt.
Dissolve above obtained compound in water and methylene dichloride (1:1 ratio, 5.0 Volumes) and adjusted pH: 10 to 10.5 with 20% K2CO3 at 25-30 °C then extracted into methylene dichloride and evaporated solvent under reduced pressure to obtain (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalen-1-ol free base as a liquid. To this liquid solution was added slowly 48% aqueous HBr solution at 25-30 °C, then heated to 100 °C to 110 °C and maintained for 4 hours after gradually cooled to 5 °C to10 °C solid as separated, filtered the solid to obtain (S)-6-(Propylamino)-5,6,7,8-tetrahydronaphthalen-1-ol HBr salt.
Yield: 85-90%
HPLC purity: 98.9%
Chiral HPLC purity: 98.7%.

Example-9: Process for the preparation of Rotigotine hydrochloride.
(S)-6-(Propylamino)-5,6,7,8-tetrahydronaphthalen-1-ol HBr salt was dissolved in water and methylene dichloride (1:1 ratio, 5.0 Volumes) and adjusted pH: 10 to 10.5 with triethyl amine at 25 to 30 °C then extracted into methylene dichloride and evaporated solvent under reduced pressure to obtain (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalen-1-ol free base as a liquid. Solution of 2-Thiophene acetic acid (6.2 equivalents) in toluene were added NaBH4 (3.2 equivalents) at 0 to 10 °C, then added above free base solution in toluene at 25 to 30 °C. Then heated to 100 °C maintained for 4 hours and monitored by TLC/HPLC. Added 20% K2CO3 to the reaction mixture extracted with toluene and evaporated under reduced pressure at 45 °C. To this crude were added methylene dichloride and purged dry HCl gas for 30 minutes at 10 °C solid formed, then filtered the solid washed with methylene dichloride to obtain Rotigotine HCl salt.
Yield: 85-90%
HPLC purity: 99.0%
Chiral HPLC purity: 99.1%.

Example-10: Process for the preparation of Rotigotine.
Rotigotine HCl salt was dissolved in water and ethyl acetate (1:1 ratio, 5.0 Volumes) and adjusted pH: 10 to 10.5 with aqueous ammonia solution at 25 to 30 °C then extracted into ethyl acetate and evaporated solvent under reduced pressure to obtain free base as a liquid. Added cyclohexane (100 mL) to this liquid compound and stirred for 2 hours solid was formed, filtered the solid and washed with ethyl acetate to obtain Form-II of Rotigotine as a white colour solid.
Yield: 85-90%
HPLC purity: 99.0%.
Chiral HPLC purity: 99.9%.
,CLAIMS:1. An improved process for the preparation of Rotigotine compound of Formula I with resolving agents, which comprises:

i. reacting 5-methoxy-2-tetralone compound of Formula II

with n-propyl amine in presence of an acid in a solvent to obtain compound of Formula III(a)

Formula III(a) is reacted in-situ with a reducing agent to obtain compound of Formula III(b)

Formula III(b) is reacted in-situ with an acid in a solvent to obtain compound of Formula III(c)

desalination of compound of Formula III(c) in presence of base and solvent to obtain compound of Formula III(d)

treating the compound of Formula III(d) with compound of formula IV to obtain optically active compound of Formula V

Wherein R is selected from

ii. demethylating of compound of Formula V in presence of base in a solvent followed by reacting with hydrobromic acid to obtain compound of Formula VI

iii. reacting the compound of Formula VI with 2-thienylacetic acid in presence of base in a solvent to obtain Rotigotine hydrochloride salt of Formula VII

iv. treating the Rotigotine hydrochloride salt of Formula VII with aqueous ammonia in a solvent to obtain Rotigotine compound of Formula I.