WO2024260959A1

WO2024260959A1 - Process for preparing optically active secondary amines and their use as intermediates

Info

Publication number: WO2024260959A1
Application number: PCT/EP2024/066908
Authority: WO
Inventors: Lidia Ozores Viturro; Alejandro GÓMEZ PALOMINO; Sergio RODRÍGUEZ ROPERO
Original assignee: Inke SA
Current assignee: Inke SA
Priority date: 2023-06-19
Filing date: 2024-06-18
Publication date: 2024-12-26
Anticipated expiration: 2025-12-19

Abstract

The present invention relates to an improved process for preparing optically active secondary amines, or a pharmaceutically or veterinary acceptable salt thereof, in high yield and high purity involving (2-naphthoyl)-L-proline as chiral resolving agent. The invention also relates to the use of (2-naphthoyl)-L-proline as chiral resolving agent of secondary amines, preferably of amine compounds of formula (I), wherein R₁ is H, C1- C₄ alkyl, preferably R¹is methyl; and R2 is C₁-C₄ alkyl, preferably R² is n-propyl and the use of the obtained optically amine compounds of formula (IV) for the preparation of rotigotine.

Description

PROCESS FOR PREPARING OPTICALLY ACTIVE SECONDARY AMINES AND THEIR USE AS INTERMEDIATES

FIELD OF THE INVENTION

The present invention relates to an improved process for preparing optically active secondary amines, or a pharmaceutically or veterinary acceptable salts thereof, in high yield and high purity involving (2-naphthoyl)-L-proline as chiral resolving agent. The invention also relates to the use of (2-naphthoyl)-L-proline as chiral resolving agent of secondary amines, preferably of amine compounds of formula (I), wherein R¹ is H, Ci- 04 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R² is n-propyl and the use of the optically amine compounds of formula (IV) for the preparation of rotigotine.

(I) (IV)

BACKGROUND OF THE INVENTION

Secondary /V-alkyl-5-alkoxy-1 ,2,3,4-tetrahydronaphthalen-2-amines and /V-alkyl-5- hydroxy-1 ,2,3,4-tetrahydronaphthalen-2-amines of formula (I) and formula (IV) have been described in the art as useful intermediates in the preparation of pharmaceutically active ingredients such as rotigotine.

Rotigotine, i.e. (6S)-6-{/V-propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8-tetrahydro-1- naphthalenol is a compound of formula (VII), is a non-ergolinic dopamine agonist for the treatment of signs and symptoms of Parkinson’s disease and idiopathic Restless Legs Syndrome.

Rotigotine is approved as a transdermal system (patch) in six strengths delivering a nominal dose of 1 mg, 2 mg, 3 mg, 4 mg, 6 mg and 8 mg each per 24 hours under the tradename Neupro.

WO 90/13294 A1 discloses the resolution of (+) and (-) isomers of 2-(/V-propylamino)-5- methoxytetralin (a secondary amine of formula (I)), with a chiral cyclic phosphoric acid, e.g., 4-(2-chlorophenyl)-5,5-dimethyl-2-hydroxy-1 ,3,2-dioxaphosphorinane-2-oxide, in a mixture of ethanol and water. Although this cyclic phosphoric acid is commercially available, its manufacturing process involves the optical resolution of the acid followed by a purification step which increases the cost of the process.

WO 91/01957 A1 discloses a process for resolving racemic 2-(/V-propylamino)-5 methoxytetralin which comprises treating it with a chiral diaroyltartaric acid, such as chiral diaroyltartaric acid is dibenzoyl-(-)-tartaric acid or diaroyltartaric acid is dibenzoyl-(+)- tartaric acid, in an organic solvent at an elevated temperature to form a salt of the amine and chiral diaroyltartaric acid which is soluble in the solvent at elevated temperature, cooling to precipitate the salt, and isolating it. According to example I, a 27.5% yield of the corresponding salt is obtained after two recrystallization steps and using 0.98 equivalents of the chiral diaroyltartaric acid. By reproducing this method, the corresponding diastereomeric salts precipitated like a “paste” difficult to filtrate.

WO 2010/043571 A1 discloses a process for resolving racemic 2-(/V-propylamino)-5 methoxytetralin which comprises /\/-(3,5-dinitrobenzoyl)-a-phenylglycine. According to example 1 , an enantiomer ratio of 83:17 of the corresponding salt with a yield of 38% is obtained. The yield decreases to a 15% after three recrystallizations to give a ratio of enantiomeric excess of 99.5%. Additionally, the use of di-nitro derivatives such as /V- (3,5-dinitrobenzoyl)-a-phenylglycine should be avoided at industrial scale for safety reasons.

Therefore, there is a need for an efficient and robust process for the optical resolution of secondary amines of formula (I) in high yield and high chemical and enantiomeric purity.

SUMMARY OF THE INVENTION

The present inventors treated racemic compounds of formula (I), wherein R¹ is H, C1-C4 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R² is n-propyl, with derivatives of L-proline as resolving agents (see compounds (ll-a), (ll-b), (ll-c), (ll-d) and (I l-e) in Scheme 1).

Scheme 1

However, diastereomeric salts in solid form were only obtained with (2-naphthoyl)-L- proline (ll-b) and biphenyl-L-proline (ll-a) after several attempts and trying different conditions and solvents. The present inventors surprisingly found that higher balance between yield and enantiomeric excess was obtained with (2-naphthoyl)-L-proline (ll-b) as chiral resolving agent compared to biphenyl-L-proline (ll-a); or compared to known prior art resolving agents such as dibenzoyl-(+/-)-tartaric acids, or (+)-/V-(3,5- dinitrobenzoyl)-a-phenylglycine.

Advantageously, the (2-naphthoyl)-L-proline (ll-b) resolves secondary amines of formula (I), wherein R¹ is H, C1-C4 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R² is n-propyl, in high yield and high enantiomeric excess, without the need for subsequent recrystallization steps that increase the cost of the overall industrial process. When compounds of formula (I) wherein R² is n-propyl are resolved using compound of formula (ll-b), the enantiomerically enriched compound of formula (I) can advantageously be used for the preparation of rotigotine (compound of formula (VII) in high yield and high enantiomeric excess.

Therefore, a first aspect of the present invention relates to a process for the preparation of optically active secondary amines, or a pharmaceutically or veterinary acceptable salt thereof, compounds of formula (IV),

(IV), wherein R¹ is H, C1-C4 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R² is n-propyl, which comprises the optical resolution of compounds of formula (I)

(I), wherein R¹ and R² is as defined above, with (2-naphthoyl)-L-proline (compound of formula (ll-b)), named also 1-(2- naphthalenylcarbonyl)-L-proline, in the presence of a solvent or a mixture of solvents.

The above-mentioned process is illustrated in Scheme 2.

Scheme 2 A second aspect of the invention refers to compounds of formula (III), particularly to (S)-

5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt, compound of formula (lll-b) wherein R¹ is methyl and R² is n-propyl.

(lll-b)

A third aspect of the invention refers to the use of compound of formula (I ll-b), (S)-5- methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt, for the preparation of (6S)-(-)-5,6,7,8-tetrahydro-6-[N-propyl-(2-thienyl)ethyl]amino-1- naphthol (rotigotine), or a pharmaceutically or veterinary acceptable salt thereof.

A fourth aspect of the invention refers to use of compound of formula (IV-a) wherein R¹ is methyl and R² is n-propyl or of compound (V-a) wherein R¹ is H and R² is n-propyl for the preparation of rotigotine, or a pharmaceutically or veterinary acceptable salt thereof.

A fifth aspect of the invention refers to a process for the preparation of (2-naphthoyl)-L- proline (compound of formula (ll-b)).

A sixth aspect of the invention refers to the use of (2-naphthoyl)-L-proline (compound of formula (ll-b)) as chiral resolving agent of secondary amines of formula (I), wherein R¹ is H, C1-C4 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R² is n-propyl.

A seventh aspect of the invention refers to a process for the preparation of Rotigotine or a pharmaceutically or veterinary acceptable salt thereof comprising the optical resolution of compound of formula (I) wherein R¹ is methyl and R² is n-propyl, with (2-naphthoyl)- L-proline, compound of formula (lib), in the presence of a solvent ora mixture of solvents. DEFINITIONS

When describing the compounds and methods of the invention, the following terms have the following meanings, unless otherwise indicated.

As used herein, “alkyl” means straight-chain or branched hydrocarbon chain radical containing no unsaturation having from 1 to 4 carbon atoms, represented as C1-C4 alkyl. Such alkyl groups may be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

The term “about” as used herein refers to a statistically meaningful range of a value, typically within 10%. Such a range can lie within experimental error, typical of standard methods used for the measurement and/or determination of a given value or range. In one embodiment, the range is within 5% of the indicated value. In another embodiment, the range is within 1% of the indicated value. In yet another embodiment, the range is within 0.5% of the indicated value.

As used herein the term “organic solvent” refers to an organic molecule capable of at least partially dissolving another substance (i.e., the solute). Organic solvents may be liquids at room temperature. Suitable organic solvents may be, but are not limited to: hydrocarbon solvents, preferably (Ci-Ci2)hydrocarbon solvents (e.g., n-pentane, n- hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes aromatic hydrocarbon solvents, preferably (Ce-Ci4)aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, 3- pentanone, etc.), ether solvents, preferably (Ci-Ci2)ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetra hydrofuran, 1 ,4-dioxane, anisole, etc.), amine solvents (e.g., propyl amine, diethylamine, triethylamine, aniline, pyridine), alcohol solvents, preferably (Ci-Ci2)alcohol solvents (e.g., methanol, ethanol, isopropanol, 1 -propanol, 2-methyl-1 -propanol, 1 -butanol, 2- butanol, 1 -pentanol, 3-methyl-1 -butanol, tert-butanol, 1 -octanol, benzylalcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc.), acid solvents (e.g., acetic acid, hexanoic acid, etc.), carbon disulfide, nitrobenzene, /V,/V- dimethylformamide, /V,/V, -dimethylacetamide, dimethyl sulfoxide, /V-methyl-2- pyrrolidone, and acetonitrile. In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents.

The term “alcohol” refers to a hydrocarbon derivative in which one or more hydrogen atoms have been replaced by an -OH group, known as hydroxyl group. Suitable alcohols for the present invention include linear, cyclic or branched Ci-Ce alkyl alcohols and any mixtures thereof. It also includes commercially available alcohols. Examples of alcohols are methanol, ethanol, isopropanol, 1-propanol and 1-butanol.

As used herein, the term “solvent extraction” refers to the process of separating components of a mixture by using a solvent which possesses greater affinity for one component and may, therefore, separate said one component from at least a second component which is less miscible than said one component with said solvent.

The term “filtration” refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid. The expression filtrate refers to the mixture less the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size. The expression filter cake refers to residual solid material remaining on a feed side of a filtration element.

The term “evaporation” refers to the change in state of solvent from liquid to gas and removal of that gas from the reactor. Various solvents may be evaporated during the synthetic route disclosed herein. As known to those of skilled in the art, each solvent may have a different evaporation time and/or temperature.

The term “phase separation” refers to a solution or mixture having at least two physically distinct regions.

The term “crystallization” refers to any method known to a person skilled in the art such as crystallization from single solvent or combination of solvents by dissolving the compound, optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as dissolving the compound in a solvent and precipitating it by addition of an “antisolvent” (i.e. a solvent in which the desired compound has low solubility or insolubility, and can be used to precipitate such compound by adding it to a solution in which the compound is dissolved).

The terms “conventional isolation techniques” or “purification” as used herein refers to the process of rendering a product clean of foreign elements whereby a purified product can be obtained. The term industrial purification refers to purifications which can be carried out on an industrial scale such as solvent extraction, filtration, slurring, washing, phase separation, distillation, centrifugation or crystallization.

The term “pharmaceutically or veterinary acceptable salt” refers to a salt prepared from an acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically acceptable inorganic or organic acids. Suitable inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Suitable organic acid is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, benzoic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleic acid, pamoic acid, aspartic acid, benzene sulfonic acid, methane sulfonic acid, ethane sulfonic acid, hydroxymethane sulfonic acid, hydroxyethane sulfonic acid, p-toluenesulfonic acid, and naphthalene-1 ,5-disulfonic acid.

The term "micronization" refers to the process of reducing the average diameter of a solid material’s particles. Usually, the term micronization is used when the particles that are produced are only a few micrometres (typically less than 10 pm) in diameter. Traditional micronization techniques are based on the use of friction to reduce particle size. Such methods include milling and grinding. Reduction in particle size may also take place as a result of collision and impact of the particles to each other.

BRIEF DESCRIPTION OF THE FIGURES

Examples of the invention are illustrated with the following drawings: FIG. 1 provides a representative ¹H-RMN plot of (S)-5-methoxy-/V-propyl-1 , 2,3,4- tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt (lll-b) obtained in Example 4.

FIG. 2 provides a representative ¹H-RMN plot of (S)-5-methoxy-/V-propyl-1 , 2,3,4- tetrahydronaphthalen-2-amine, (biphenyl)-L-prolinate salt obtained in Comparative example 1 , entry 4.

FIG. 3 provides a representative Thermal Gravimetric Analysis (TGA) plot of (S)-5- methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt obtained in Example 4.

FIG. 4 provides a representative Differential Scanning Calorimetry (DSC) of (S)-5- methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt obtained in Example 4.

FIG. 5 provides a representative infrared absorption spectrum (IR) of (S)-5-methoxy-N- propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt obtained in Example 4.

DETAILED DESCRIPTION OF THE INVENTION

According to the first aspect, the molar ratio of (2-naphthoyl)-L-proline (compound (I l-b)) to compound of formula (I), wherein R¹ is H, C1-C4 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R² is n-propyl, may be from 0.5 to 1.2 equivalents, preferably from 0.6 to 1.0 equivalents, more preferably from 0.7 to 0.9 equivalents, even more preferably is about 0.7 equivalents.

In certain embodiments, racemic 2-(/V-propylamino)-5-methoxytetralin, compound of formula (I), wherein R¹ is methyl and R² is n-propyl, may be prepared according to Method II, step 1 of prior art US4564628 A. In certain embodiments, the hydrochloride salt of 2-(/V-propylamino)-5-methoxytetralin is used and neutralised with a base, such as an inorganic base (e.g., an alkali metal carbonate) in a suitable solvent, preferably an organic solvent selected from a hydrocarbon solvent such as toluene or an ether solvent such as tetra hydrofuran and 2-methyltetrahydrofuran. In certain embodiments, the hydrochloride salt of 2-(/V-propylamino)-5-methoxytetralin is neutralised with potassium carbonate in toluene, preferably at 50-60 °C to provide a solution, following with extraction of the 2-(/V-propylamino)-5-methoxytetralin. In certain embodiments, the molar ratio of (2-naphthoyl)-L-proline (compound of formula (ll-b)) to compound of formula (III), wherein R¹ is H, C1-C4 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R2 is n-propyl, more preferably wherein R¹ is methyl and R² is n-propyl, is from 0.6 to 1.0 equivalents, preferably from 0.7 to 0.9 equivalents.

In certain embodiments, the solvent may be a mixture comprising an organic solvent and water, preferably water and a water-miscible organic solvent. Suitable organic solvent may be selected from an alcohol solvent, a ketone solvent, an ether solvent and acetonitrile. In certain embodiments, the organic solvent is selected from acetonitrile, acetone, ethanol, isopropanol, and tetrahydrofuran. In certain embodiments, the solvent is a mixture of acetonitrile and water.

In certain embodiments, the mixture of an organic solvent and water is from 15:1 v/v to 5:1 v/v, preferably from 10:1 v/v to 7:1 v/v, more preferably is about 8:1 v/v.

In certain embodiments, the solvent of the first aspect is a mixture of acetonitrile and water in about 8:1 v/v.

In certain embodiments, the temperature of first aspect is from 25 °C to 100 °C, preferably 20 °C to 100 °C, preferably from 50 °C to 85 °C, more preferably about 80 °C, to provide a solution. In certain embodiments, the resulting solution may be cooled down to about 70 °C, at a cooling rate of about 5 °C/10 min. In certain embodiments, the resulting solution may be seeded with the corresponding diastereomeric salt to facilitate the nucleation. In certain embodiments, the resulting mixture may be cooled down to about 25 °C, about 20 °C, about 15 °C, about 10 °C, about 5 °C, about 0 °C, to allow precipitation of the corresponding diastereomeric salt. In certain embodiments, the corresponding diastereomeric salt may be isolated by conventional isolation techniques and/or purified by crystallization.

Advantageously, the optical resolution process of the first aspect which involves the (2- naphthoyl)-L-proline (compound of formula (ll-b)) as chiral resolving agent provides the corresponding diastereomeric salts of compounds of formula (III), wherein R¹ is H, Ci- 04 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R² is n-propyl, with a proportion of S/R enantiomer ratio higher than or equal to 95:5, preferably higher than or equal to 97:3, more preferably higher than or equal to 98:2, even more preferably higher than or equal to 99:1 in the first crystallization.

According to the second aspect of the invention, the (S)-5-methoxy-/V-propyl-1 , 2,3,4- tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt, compound of formula (III- b), wherein R¹ is methyl and R² is n-propyl, crystallizes in high chemical purity and having a proportion of S/R enantiomer ratio higher than or equal to 95:5, preferably higher than or equal to 97:3, more preferably higher than or equal to 98:2, even more preferably higher than or equal to 99:1 in the first crystallization.

(lll-b)

In certain embodiments, diastereomeric salts of compounds of formula (III), wherein R¹ is H, C1-C4 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R² is n-propyl, more preferably the (S)-5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2- naphthoyl)-L-prolinate salt, compound of formula (lll-b), may be recrystallized in a suitable solvent. In certain embodiments, the solvent may be a mixture of solvents which comprises an organic solvent and water. Suitable organic solvent may be selected from an alcohol solvent, a ketone solvent, an ether solvent and acetonitrile. In certain embodiments, the organic solvent is selected from acetonitrile, acetone, ethanol, isopropanol, and tetra hydrofuran. In certain embodiments, the solvent is a mixture of acetonitrile and water. In certain embodiments, the mixture of an organic solvent and water is from 15:1 (v/v) to 5:1 (v/v). In certain embodiments, the organic solvent is a mixture of isopropanol and water in a ratio about 6:1 (v/v). In certain embodiments, the organic solvent is a mixture of acetonitrile and water in a ratio about 8:1 (v/v).

In certain embodiments, the diastereomeric salts compounds of formula (III) need not necessarily be dried but may also be used moist in the subsequent steps. In certain embodiments, the diastereomeric salts compounds of formula (III) may be isolated and dried. Another aspect refers to the use of the diastereomeric salt of the compound of formula (lll-b), (S)-5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2-naphthoyl)-L- prolinate salt, as intermediate in the preparation of (6S)-(-)-5,6,7,8-tetrahydro-6-[/V- propyl-(2-thienyl)ethyl]amino-1-naphthol (rotigotine), or a pharmaceutically or veterinary acceptable salt thereof.

Another aspect of the invention, the (S)-5-hydroxy-/V-propyl-1 , 2,3,4- tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt compound of formula (III- a), wherein R¹ is H and R² is n-propyl, crystallizes in high chemical purity and having a proportion of S/R enantiomer ratio higher than or equal to 95:5, preferably higher than or equal to 97:3, more preferably higher than or equal to 98:2, even more preferably higher than or equal to 99:1 in the first crystallization.

(lll-a)

In certain embodiments, the (S)-5-hydroxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2- amine, (2-naphthoyl)-L-prolinate salt, compound of formula (lll-a), may be recrystallized in a suitable solvent. Suitable organic solvent may be selected from an alcohol solvent, a ketone solvent, an ether solvent and acetonitrile. In certain embodiments, the organic solvent is selected from acetonitrile, acetone, ethanol, isopropanol, and tetrahydrofuran. In certain embodiments, the solvent is a mixture of acetonitrile and water. In certain embodiments, the mixture of an organic solvent and water is from 15:1 (v/v) to 5:1 (v/v). In certain embodiments, the solvent is a mixture of isopropanol and water in a ratio about 6:1 (v/v).

Another aspect refers to the use of the diastereomeric salt of the compound of formula (lll-a) as intermediate in the preparation of (6S)-(-)-5,6,7,8-tetrahydro-6-[/V-propyl-(2- thienyl)ethyl]amino-1 -naphthol (rotigotine), or a pharmaceutically or veterinary acceptable salt thereof.

In certain embodiments, the diastereomeric salts compounds of formula (III) deriving from the amine compounds of formula (I) and the (2-naphthoyl)-L-proline are isolated and neutralized with a base to provide compounds of formula (IV). Suitable bases may be inorganic bases selected from hydroxides, carbonates and hydrogen carbonates of an alkali metal such as sodium or potassium and an alkali earth metal such as calcium or magnesium, and mixtures thereof. In certain embodiments, the diastereomeric salt of compounds of formula (III) may be neutralized with a base, such as an inorganic base (e.g., an alkali metal carbonate) in a suitable solvent such as toluene or an ether solvent such as tetra hydrofuran and 2-methyltetrahydrofuran to provide the compound of formula (IV), wherein R¹ is H, C1-C4 alkyl, preferably R¹ is methyl and R2 is C1-C4 alkyl, preferably R² is n-propyl. In certain embodiments, the precipitated (S)-5-methoxy-/V- propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt, compound of formula (Illa) is isolated and neutralized with a base to provide compound (IV) wherein R1 is methyl; and R2 is C1-C4 alkyl, preferably R2 is n-propyl.

In certain embodiments, compound of formula (IV), wherein R¹ is C1-C4 alkyl, preferably R¹ is methyl, and R² is C1-C4 alkyl, preferably R² is n-propyl, may be demethylated in the presence of hydrobromic acid to provide the hydrobromide salt of compound of formula (V), wherein R1 is H and R2 is C1-C4 alkyl, preferably R2 is n-propyl.

In certain embodiments, the corresponding hydrobromide salt of compound of formula (V), wherein R1 is H and R2 is C1-C4 alkyl, preferably R2 is n-propyl, may be treated with a hydride source, preferably sodium borohydride, and 2-(thiophen-2-yl)acetic acid to provide optically active rotigotine.

In certain embodiments, the diastereomeric salt of compound of formula (lll-b) (Scheme 2), wherein R1 is methyl and R2 is n-propyl, is neutralised with potassium carbonate in toluene, preferably at 50-60 °C to provide a solution, following with extraction of compound of formula (IV), wherein R1 is methyl and R2 is n-propyl, which is further treated with hydrobromic acid to provide the corresponding hydrobromide salt of compound of formula (V), wherein Ri is H and R2 is n-propyl, in high purity and yield. In certain embodiments, the corresponding hydrobromide salt of compound of formula (V-a), wherein Ri is H and R2 is n-propyl, is further treated with 2-(thiophen-2-yl)acetic acid in the presence of sodium borohydride in toluene to provide rotigotine following the process disclosed in Method III of EP 0 168 505 A1 .

In certain embodiments, the corresponding hydrobromide salt of compound of formula (V-a), wherein R1 is H and R2 is n-propyl, is neutralised with a base, such as an inorganic base (e.g., an alkali metal carbonate) in a suitable solvent, preferably an organic solvent selected from a hydrocarbon solvent such as toluene or an ether solvent such as tetra hydrofuran, 2-methyltetrahydrofuran or anisole, and further treated with 2-(thiophen- 2-yl)acetic acid in the presence of sodium borohydride in toluene to provide rotigotine following the process disclosed in Method III of EP 0 168 505 A1.

In certain embodiments, the rotigotine may be treated with an acceptable pharmaceutically inorganic or organic acid to provide the corresponding pharmaceutically acceptable or veterinary salt.

In certain embodiments, the rotigotine may be treated with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, naphthalene-1 ,5-disulfonic acid, tartaric acid, and phosphoric acid.

In certain embodiments, the rotigotine base is treated with an inorganic acid which is hydrochloric acid to provide rotigotine hydrochloride salt. In certain embodiments, the polymorph of rotigotine hydrochloride salt obtained is the polymorphic form I, II, III, IV and V disclosed in prior art WO 2009/053697 A1.

In certain embodiments, the pharmaceutically acceptable or veterinary salt of rotigotine such as the hydrochloride salt of rotigotine is treated with a base to provide rotigotine.

In certain embodiments, rotigotine is crystallized by a process comprising: a) dissolving rotigotine in a solvent or a mixture of solvents, preferably a ketone solvent such as acetone, b) adding an antisolvent such as water to facilitate the precipitation, c) optionally washing the crystals of rotigotine, and d) isolating rotigotine and, e) optionally drying.

In certain embodiments, the rotigotine is crystallized by either adding of an antisolvent such as water to a solution of rotigotine in a solvent, preferably a ketone solvent such as acetone, or the addition of a solution of rotigotine in a solvent preferably a ketone solvent such as acetone to an antisolvent such as water.

In certain embodiments, the polymorph of rotigotine is the polymorphic form II disclosed in WO 2009/068520 A1.

In certain embodiments, the rotigotine base may be micronized to control or reduce the particle size.

According to the fifth aspect of the invention, the process for the preparation of (2- naphthoyl)-L-proline, compound of formula (ll-b) comprises:

(ll-b), a) reacting L-proline with compound of formula (VIII)

(VIII), wherein G is OH, Cl, Br, preferably G is Cl, in the presence of a solvent, and optionally in the presence of an inorganic base. b) isolating (2-naphthoyl)-L-proline (ll-b), and optionally drying (2-naphthoyl)-L-proline thus obtained.

Suitable solvent in step (a) may be an aromatic hydrocarbon solvent, preferably an (Ce- Ci4)aromatic hydrocarbon solvent selected from toluene, o-xylene, m-xylene and p- xylene and mixtures thereof. Suitable inorganic base may be an alkali metal hydroxide such as sodium or potassium, preferably used in aqueous solution.

In certain embodiments, (2-naphthoyl)-L-proline (ll-b) is prepared from compound of formula (V), wherein G is Cl, in the presence of sodium hydroxide and in a mixture of toluene and water.

Step (b) is carried out by methods known to the person skilled in the art, for example by filtration or using a centrifuge. In certain embodiments, the solid (b) may be dried or used moist in the resolution step.

In certain embodiments, the isolated (2-naphthoyl)-L-proline obtained in step (b) is further dissolved or suspended in an ester solvent selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and ethyl malonate, since the impurities are reduced.

In certain embodiments, the process for the preparation of (2-naphthoyl)-L-proline, compound of formula (ll-b) comprises a previous step of treating 2-naphthoic acid with a chlorinating agent to provide compound (VIII) wherein G is Cl.

In certain embodiments, 2-naphthoic acid is reacted with a chlorinating agent such as thionyl chloride (SOCh) to provide freshly compound (VIII) wherein G is Cl, which is further reacted with L-proline in the presence of a solvent.

Another aspect relates to the use of the (2-naphthoyl)-L-proline, compound of formula (ll-b), as chiral resolving agent of secondary amines, preferably of compounds of formula (I),

(I), wherein R¹ is H, C1-C4 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R² is n-propyl, more preferably R¹ is methyl and R² is n-propyl.

In the following, the present invention is further illustrated by examples. They should in no case be interpreted as a limitation of the scope of the invention as defined in the claims. Unless indicated otherwise, all indications of percentage are by weight and temperatures are in degrees Celsius. GENERAL METHODS

The compounds of the present invention were characterized by common analytical techniques such as ¹H-NMR, Differential Scanning Calorimetry (DSC), Thermogravimety (TGA), Fourier Transformed Infrared spectroscopy analysis (FTIR), and High- Performance Liquid Chromatography (HPLC) using the following methods:

Proton nuclear magnetic resonance (¹H-NMR)

Sample preparation: Approximately 2-5 mg of sample were dissolved in 0.7 mL of deuterated solvent.

Data acquisition: Proton nuclear magnetic resonance analyses were recorded in a Bruker 400 NMR spectrometer, equipped with a z gradient 5 mm BBO (Broadband Observe) probe with ATM and an automatic autosampler.

Measurement conditions: The samples were analyzed at room temperature.

Differential Scanning Calorimetry (DSC)

Sample preparation: Approximately 1-4 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 pL aluminium crucibles with a pinhole lid.

Data acquisition: DSC analyses were recorded in a Mettler Toledo DSC822e calorimeter. Programs used: Data collection and evaluation with software STARe.

Measurement conditions: The samples were heated under dry nitrogen (flow rate: 50 mL/min) at 10 °C/min from 30 to 300 °C.

Thermal Gravimetric Analysis (TGA)

Data acquisition: Thermogravimetric analyses were recorded in a Mettler Toledo TGA/DSC 3+ with a balance XP1 type. Programs used: Data collection and evaluation with software STARe.

Measurement conditions: The samples were heated under dry nitrogen (flow rate: 10 mL/min) at 10 °C/min from 30 to 300 °C.

Fourier Transformed Infrared spectroscopy analysis (FTIR)

The FTIR spectra were recorded using an Agilent Technologies Cary 630 FTIR spectrometer, equipped with an Agilent Diamond single reflection ATR system, a mid- infrared source as the excitation source and a DTGS detector. The spectra were acquired in 32 scans at a resolution of 4 cm^-1 in the range of 4000- 650 cm^-1.

HPLC METHODS

HPLC method for determining chemical purity

Column: Zorbax Rx-C8

Dimensions: 15 cm x 0.46 mm ID x 5 pm

Sample preparation: 2.0 mg/ mL in H2O:Acetonitrile (30:70)

Flow: 1.4 mL/min

Wavelength: 210 nm

Column Temperature: 40 °C

Injection volume: 5 pL

Mobile phase A: 10 mM KH2PO4, add 1 mL of triethylamine to a 1000 mL of water. Adjust pH to 5.5±0.1 with phosphoric acid.

Mobile phase B: Acetonitrile

Time of analysis: 35.1 minutes

Elution: Gradient (Table 1)

Table 1

HPLC method for determining enantiomeric purity of (2-naphthoyl)-L-proline (compound ll-b)

Column: Amylose tris (3-chlorophenylcarbamate) immobilized on 3 pm silica-gel (CHIRALCEL-ID3)

Dimensions: 4.6 mm x 250 mm x 3 pm

Sample preparation: 1 mg/mL in methanol

Flow: 1.2 mL/min

Wavelength: 225 nm

Column Temperature: 25°C

Injection volume: 5 pL

Mobile phase: n-Hexane:Ethanol:Methanol:TFA (80:10:10:0.1)

Time of analysis: 15 minutes HPLC method for determining enantiomeric purity of diastereomeric salt (compound III)

Column: Cellulose tris(3,5-dimethylphenylcarbamate) coated on 10 pm silica-gel (CHIRALCEL-OD)

Dimensions: 4.6 mm x 250 mm x 10 pm

Sample preparation: 2 mg/mL in Phase B

Flow: 0.8 mL/min

Wavelength: 225 nm

Column Temperature: 35 °C

Injection volume: 10 pL

Mobile phase: n-Hexane: Phase A:DEA:TFA (93:7:0.1:0.05)

Phase A: Ethanol:Methanol:2-Propanol (90:5:5)

Phase B: Phase A + 0.1 % DEA + 0.05 % TFA

Time of analysis: 60 minutes

For the determination of the enantiomeric purity of diastereomeric salt (compound III) prepared in examples 7, 8 and 9, the above HPLC method was modified as follows: Mobile phase: n-Hexane: Phase A: DEA:TFA (94:6:0.1 :0.05)

Injection volume: 15 pL

Sample preparation: 2 mg/mL in methanol

Time of analysis: 65 minutes

HPLC method for determining enantiomeric purity of (S)-6-(/V-propylamino)- 5,6,7,8-tetrahydronaphthalen-1-ol or salts thereof, preferably hydrobromide salt

Dimensions: 4.6 mm x 250 mm x 10 pm

Sample preparation: 3 mg/mL in Phase B

Flow: 1.0 mL/min

Wavelength: 225 nm

Column Temperature: 25°C

Injection volume: 10 pL

Mobile phase: n-Hexane: Phase A:DEA:TFA (93:7:0.1:0.05)

Phase A: Ethanol:Methanol:2-Propanol (90:5:5)

Phase B: Phase A + 0.1 % DEA + 0.05 % TFA

Time of analysis: 25 minutes EXAMPLES

Example 1 : Preparation of (2-naphthoyl)-L-proline (ll-b)

A stirred solution of L-proline (50.00 g, 1 equiv., 434.3 mmol) in water (150 mL) was treated with a solution of sodium hydroxide (34.74 g, 2.0 equiv., 868.6 mmol) in water (175 mL) at 25 °C. Then, a solution of 2-naphthoyl chloride (82.79 g, 1.0 equiv., 434.3 mmol) in toluene (125 mL) was added dropwise under vigorous stirring. The biphasic mixture was stirred for 1-2 hours at 25 °C. Hydrochloric acid 37 % (60 mL) was used to adjust the pH to 1-2 and the resulting suspension was stirred for 2 hours at the same temperature. The suspension was filtered off and the resulting solid was purified in toluene at reflux, filtered off and dried.

Yield: 110.6 g (95 %)

HPLC: 99.4 % (S/R enantiomer ratio of 99.7:0.3)

Example 2: Preparation of (2-naphthoyl)-L-proline (ll-b)

A suspension of 2-naphthoic acid (100.00 g, 0.58 mol) in toluene (400 mL) and SOCh (63.6 mL, 1.5 equiv., 0.87 mol) was heated at 90 °C for 4 h. Excess of SOCh was removed by distillation under vacuum and the resulting residue was codistilled with toluene (100 mL). The obtained 2-naphthoyl chloride was dissolved in toluene (170 mL) and reserved. Then, a stirred solution of L-proline (66.87 g, 1 .0 equiv., 0.58 mol) in water (230 mL) was treated with an aqueous solution of NaOH 20 % w/w (190 mL, 2 equiv., 1.16 mol) at 25 °C. Next, the previously prepared fresh solution of 2-naphthoyl chloride was added dropwise under vigorous stirring. The biphasic mixture was stirred for 2 h at 25°C. The organic phase was removed by decantation and the aqueous phase was acidified to pH 2 with HCI 6M at 25 °C. The resulting suspension was stirred for 2 h at the same temperature, filtered and washed with water and ethyl acetate. The wet cake was purified in ethyl acetate at reflux, filtered and dried.

Yield: 136.13 g (87 %)

HPLC: 99.9 % (S/R enantiomer ratio of 99.7:0.3)

Example 3. Preparation of 5-methoxy-ALpropyl-1,2,3,4-tetrahydronaphthalen-2- amine hydrochloride

Acetic acid (385.0 mL, 7.9 equiv., 6.73 mol) was added dropwise to a suspension of NaBH4 (45.08 g, 1.40 equiv., 1.19 mol) in tetrahydrofuran (1.00 L) at 10 °C. Then, the suspension was stirred for 45 min at 25 °C and cooled to 10 °C. Next, propylamine (84.0 mL, 1.2 equiv., 1.02 mol) followed by a solution of 5-methoxy-3,4-dihydronaphthalen- 2(1/-/)-one (150.00 g, 1 equiv., 0.85 mol) in tetra hydrofuran (150 mL) were added at 10 °C. The reaction was stirred for 2 h at 25 °C. After, the mixture was cooled to 10 °C, acidified to pH 2 with HCI 6M and stirred for 3 h at 10 °C. The resulting suspension was filtered, washed with tetrahydrofuran. The obtained wet solid was suspended in 2- MeTHF (600 mL) and K2CO3 20 % w/w (1.5 L) and stirred at 60 °C until complete dissolution. The layers were separated, the aqueous layer was washed with 2-MeTHF and the combined organic layers were washed with water. The organic fraction was cooled to 10 °C, acidified to pH 2 with HCI 6M and stirred for 3 h at 10 °C. The resulting suspension was filtered, washed with tetrahydrofuran and dried.

Yield: 179.89 g (83 % yield)

HPLC: 99.9 %

Example 4: Preparation of (S)-5-methoxy-/V-propyl-1,2,3,4-tetrahydronaphthalen- 2-amine, (2-naphthoyl)-L-prolinate salt (lll-b)

A stirred suspension of racemic 5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2- amine hydrochloride (11.8 g, 1 equiv., 46.0 mmol) in toluene (90 mL) and K2CO3 10 % w/w (117 mL, 2.0 equiv., 92.0 mmol) was heated to 60 °C until complete dissolution. The layers were separated, and the aqueous layer was washed with toluene (30 mL). The combined organic layers were concentrated under vacuum and codistilled with acetonitrile (30 mL). The obtained freebase 5-methoxy-/V-propyl-1 , 2,3,4- tetrahydronaphthalen-2-amine residue was dissolved in acetonitrile (10 mL) and heated to 60 °C. Then, a solution of 2-naphthoyl)-L-proline (8.67 g, 0.7 equiv., 32.2 mmol; prepared as in Example 1) in a mixture of acetonitrile/H2O (30 mL/5 mL) was added dropwise. Then, acetonitrile/H2O (40 mL/5 mL) were added and heated to reflux until complete dissolution. The solution was slowly cooled to 0-5 °C and stirred for 0.5-1 h. The suspension was filtered off and the resulting solid was oven dried.

Yield: 7.29 g (32 %)

HPLC: 99.9% (S/R enantiomer ratio of 98.6:1.4)

Melting Point (DSC onset): 207.29 °C

TGA: anhydrous, non-solvate.

IR (cm-¹, KBr): 2933, 2876, 2828, 1611 , 1597, 1588, 1558, 1468, 1435, 1388, 1342, 1254, 1099, 812, 765, 750, 658, 478. ¹H NMR (400 MHz, CDCI₃) 6 8.20 (br s, 2H), 7.98 (s, 1 H), 7.88 - 7.23 (m, 6H), 7.04 (t, J = 7.9 Hz, 1 H), 6.59 (dd, J = 21.0, 7.9 Hz, 2H), 4.72 - 4.22 (m*, 1 H), 3.98 - 3.58 (m, 2H), 3.79 (s, 3H), 3.53 - 3.44 (m, 4.5 Hz, 1 H), 3.33 - 2.66 (m, 6H), 2.63 - 2.22 (m, 2H), 2.20 - 1.52 (m, 6H), 0.89 (t, J = 7.4 Hz, 3H).

*The multiplet comprises 2 signals of amide rotamers.

The obtained dried solid (6.0 g) was suspended in a mixture of acetonitrile/H2O heated and then cooled to 0-5 °C. The suspension was filtered off and the resulting solid was oven dried.

Yield: 4.63 g (77 %)

HPLC: 99.9 % (S/R enantiomer ratio of 99.97:0.03)

Example 5. Preparation of (S)-5-methoxy-/V-propyl-1,2,3,4-tetrahydronaphthalen-2- amine, (2-naphthoyl)-L-prolinate salt (lll-b)

A solution of (2-naphthoyl)-L-proline (compound (lib); 0.7-0.9 equiv.) in a mixture of organic solvent and H2O was added dropwise to a solution of 5-methoxy-/V-propyl- 1 ,2,3,4-tetrahydronaphthalen-2-amine (11.8 g) in of organic solvent (10 mL) from 60 °C to 80 °C. Then, the mixture was heated until complete dissolution. The resulting solution was slowly cooled to 0-5 °C and stirred for 0.5-1 h. The suspension was filtered off at 5 °C and the resulting solid was oven dried. The results are gathered in Table 2.

Table 2

Example 6. Preparation of (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalen-1-ol hydrobromide (Va)

A stirred suspension of (S)-5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt (lll-b) (60 g, 1 equiv., 0.12 mol; prepared as in example 2) in toluene (240 mL) and K2CO3 10 % w/w (0.23 L, 1.5 equiv., 0.18 mol) was heated to 60 °C until complete dissolution. The layers were separated, and the organic layer was washed with K2CO3 10 % w/w (60 mL) and H2O (60 mL). The organic layer was concentrated until the solvent was completely removed. The obtained freebase (S)-5- methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine (IV-a) residue was dissolved in AcOH (60 mL) and heated to 40 °C. Then HBr 48 % w/w (0.11 L, 8.0 equiv., 0.96 mol) was added dropwise and the mixture was heated under reflux for 3-6 hours. The resulting suspension was cooled down to 0-5 °C and stirred for 0.5-1 h. The suspension was filtered off and the resulting solid was oven dried.

Yield: 30.76 g (88 %)

HPLC: 99.4 %

Example 7. Preparation of (S)-5-methoxy-/V-propyl-1,2,3,4-tetrahydronaphthalen-2- amine, (2-naphthoyl)-L-prolinate salt (lll-b)

A stirred suspension of 5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (17.50 g, 1 equiv., 68.4 mmol) in 2-MeTHF (70 mL) and K2CO3 20 % w/w (60 mL, 1.5 equiv., 102.6 mmol) was heated to 50 °C until complete dissolution. The layers were separated, and the aqueous layer was washed with 2-MeTHF (17 mL). The combined organic layers were concentrated under vacuum and codistilled with acetonitrile (30 mL). The obtained freebase 5-methoxy-/V-propyl-1 , 2,3,4- tetrahydronaphthalen-2-amine residue was dissolved in acetonitrile (30 mL) and added slowly to a solution of (2-naphthoyl)-L-proline (11.05 g, 0.6 equiv., 41.1 mmol) in a mixture of acetonitrile/H2O (60 mL / 11.3 mL) at 50 °C. The resulting suspension was heated to reflux to ensure complete dissolution. The resulting solution was seeded and slowly cooled to 0-5 °C and stirred for 1 h. The suspension was filtered off, washed with a chilled mixture of acetonitrile/H2O, acetonitrile and dried.

Yield: 10.50 g (31 % yield)

HPLC: 99.8 % (S/F? enantiomer ratio of 99.56:0.44) Example 8. Preparation of (S)-5-methoxy-/V-propyl-1,2,3,4-tetrahydronaphthalen-2- amine, (2-naphthoyl)-L-prolinate salt (lll-b)

A stirred suspension of 5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (60.00 g, 1 equiv., 234.6 mmol) in 2-MeTHF (240 mL) and K2CO3 20 % w/w (200 mL, 1.5 equiv., 351.9 mmol), was heated to 50°C until complete dissolution. The layers were separated, and the aqueous layer was washed with 2-MeTHF (60 mL). The combined organic layers were concentrated under vacuum and codistilled with acetonitrile (60 mL). The obtained freebase 5-methoxy-/V-propyl-1 , 2,3,4- tetrahydronaphthalen-2-amine residue was dissolved in acetonitrile (200 mL) and added slowly to a solution of 2-naphthoyl)-L-proline (56.85 g, 0.9 equiv., 211.1 mmol) in a mixture of acetonitrile/H2O (280 mL I 60 mL) at 50°C. The resulting suspension was heated to reflux to ensure complete dissolution. The resulting solution was seeded and slowly cooled to 0-5°C and stirred for 1 h. The suspension was filtered off, washed with a chilled mixture of acetonitrile/H2O, acetonitrile and dried.

Yield: 41.66 g (36%)

HPLC: 99.8% SIR enantiomer ratio of 99.82:0.18)

Example 9. Preparation of (S)-5-methoxy-/V-propyl-1,2,3,4-tetrahydronaphthalen-2- amine, (2-naphthoyl)-L-prolinate salt (lll-b)

A stirred suspension of 5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (175.00 g, 1 equiv., 684.0 mmol) in 2-MeTHF (700 mL) and K2CO3 20 % w/w (600 mL, 1.5 equiv., 1.03 mol) was heated to 50 °C until complete dissolution. The layers were separated, and the aqueous layer was washed with 2-MeTHF (175 mL). The combined organic layers were concentrated under vacuum and codistilled with acetonitrile (175 mL). The obtained freebase 5-methoxy-/V-propyl-1 , 2,3,4- tetrahydronaphthalen-2-amine residue was dissolved in acetonitrile (450 mL) and added slowly to a solution of (2-naphthoyl)-L-proline (138.18 g, 0.75 equiv., 513.1 mmol) in a mixture of acetonitrile/H2O (750 mL /150 mL) at 50°C. The resulting suspension was heated to reflux to ensure complete dissolution. The resulting solution was seeded and slowly cooled to 0-5°C and stirred for 1 h. The suspension was filtered off, washed with a chilled mixture of acetonitrile/H2O, acetonitrile and dried.

Yield: 115.85 g (34%)

HPLC: 99.8 % (SIR enantiomer ratio of 99.86:0.14) Example 10: Preparation of (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalen-1-ol hydrobromide (Va)

A stirred suspension of (S)-5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt (lll-b) (75.00 g, 1 equiv., 0.15 mol) in 2-MeTHF (300 mL) and K2CO320 % w/w (135 mL, 1.5 equiv., 0.23 mol) was heated to 50 °C until complete dissolution. The layers were separated, and the organic layer was washed with an K2CO3 10 % w/w and H2O. The organic layer was concentrated until the solvent was completely removed. The freebase (S)-5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine residue was dissolved in acetic acid (60 mL) and heated to 40°C. Then HBr 48 % w/w (120 mL, 6.8 eq, 1.04 mol) was added dropwise and the mixture was heated at 100°C for 16 hours. The resulting suspension was cooled to 0-5°C and stirred for 0.5-1 h. The suspension was filtered, washed with chilled water and dried.

Yield: 38.16 g (87 % yield)

HPLC: 99.4 %

Example 11. Preparation of (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5, 6,7,8- tetrahydronaphthalen-1 -ol (rotigotine)

A stirred suspension of (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalen-1-ol hydrobromide (35.00 g, 1 equiv., 0.12 mol), in 2-MeTHF (140 mL) and K2CO3 10 % w/w (170 mL, 1.1 equiv., 0.13 mol) was heated to 40 °C until complete dissolution. The layers were separated, and the aqueous layer was washed with 2-MeTHF. The combined organic layers were concentrated under vacuum to obtain (S)-6-(propylamino)-5, 6,7,8- tetrahydronaphthalen-1-ol freebase.

In parallel, NaBH4 (15.34 g, 3.25 equiv., 397.5 mmol) was added portionwise over a suspension of thiophene-2-acetic acid (108.7 g, 6.25 equiv., 0.76 mol) in anisole (175 mL) at 10 °C. The mixture was stirred 30 min at 10 °C, and 30 min at 25 °C.

Next, a solution of the previously obtained freebase (S)-6-(propylamino)-5, 6,7,8- tetrahydronaphthalen-1-ol in anisole (75 mL) was added to the suspension and heated at 90 °C for 4 hours. Then, the reaction was cooled to 10 °C and quenched slowly with water. The mixture was treated with charcoal 5 % w/w for 1 h, filtered and washed with ethyl acetate. The filtrate was basified to pH 8 with K2CO3 20 % w/w, the layers were separated, and the organic phase washed with K2CO320 % w/w. The organic phase was cooled to 0-5 °C, seeded, acidified to pH 2 with HCI 3M in ethyl acetate and stirred at 25 °C for 4 hours. The resulting suspension was filtered and washed with ethyl acetate. The wet cake was suspended in ethyl acetate (175 mL) and K2CO3 10 % w/w (170 mL, 1.1 equiv., 0.13 mol) and heated at 40 °C until complete dissolution. The layers were separated, and the aqueous layer was washed with ethyl acetate. The combined organic layers were concentrated under vacuum.

The residue was dissolved in acetone (130 mL) at 25 °C, seeded and treated dropwise with water (400 mL). The resulting suspension was stirred for 4 h at 25 °C, filtered, washed with water and dried.

Yield: 36.65 g (95 % yield)

HPLC: 99.4 % (S/R enantiomer ratio of 100:0)

Example 12. Preparation of (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5, 6,7,8- tetrahydronaphthalen-1 -ol (rotigotine)

A stirred suspension of (S)-5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2-naphthoyl)-L-prolinate salt (8.50 g, 1 equiv., 33.2 mmol) in 2-MeTHF (34 mL) and K2CO3 10 % w/w (30 mL, 1.5 equiv., 50.0 mmol) was heated to 40 °C until complete dissolution. The layers were separated, and the organic layer was washed with K2CO3 10 % w/w and H2O. The organic layer was concentrated until the solvent was completely removed.

The freebase (S)-5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine residue was dissolved in acetic acid (15 mL) and heated to 40 °C. Then HBr 48 % w/w (23 mL, 6.0 equiv., 199 mmol) was added dropwise, and the mixture was heated to at 100 °C for 16h. The reaction mixture was cooled to 25 °C, neutralized with NaOH 20 % w/w, basified to pH 10 with K2CO3 30 % w/w and extracted with 2-MeTHF. The combined organic layers were concentrated under vacuum obtaining 5.88 g (86 % yield) of the phenol intermediate, which is used in the next step without purification.

The residue was combined with thiophene-2-acetic acid (24.43 g, 6.0 equiv., 171.8 mmol) and anisole (60 mL). The suspension was cooled to 10 °C and sodium borohydride (3.32 g, 3.0 equiv., 95.9 mmol) was added portionwise. The suspension was stirred 30 min at 10 °C, 30 min at 25 °C and 4 h at 90 °C. The reaction was cooled to 10 °C and quenched slowly with water. The mixture was treated with charcoal 5 % w/w for 1 h, filtered and washed with ethyl acetate. The filtrate was basified to pH 8 with K2CO3 20 % w/w, the layers were separated, and the organic phase washed with K2CO3 20 % w/w. The organic phase was cooled to 0-5 °C, seeded, acidified to pH 2 with HCI 3M in ethyl acetate and stirred for 4 h at 25 °C. The resulting suspension was filtered and washed with ethyl acetate. The wet cake was suspended in ethyl acetate (40 mL) and K2CO3 10 % w/w (40 mL, 1.1 equiv., 31.5 mmol) and was heated to 40 °C until complete dissolution. The layers were separated, and the aqueous layer was washed with ethyl acetate. The combined organic layers were concentrated under vacuum. The residue was dissolved in acetone (30 mL) at 25 °C, seeded and treated dropwise with water (100 mL). The resulting suspension was stirred for 4 h at 25 °C, filtered, washed with water and dried.

Yield: 8.58 g (95 % yield)

HPLC 99.4 % (S/R enantiomer ratio of 100:0)

Comparative example 1. Preparation of (S)-5-methoxy-/V-n-propyl-1,2,3,4- tetrahydronaphthalen-2-amine, (biphenyl)-L-prolinate salt (lll-c)

A solution of biphenyl-L-proline (I l-a; 0.6 equiv.) in a mixture of organic solvent and H2O was added dropwise to a solution of 5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen- 2-amine (2 g) in of organic solvent (3-5 mL) from 60 °C to 80 °C. Then, the mixture was heated until complete dissolution. The resulting solution was slowly cooled to 0-5 °C and stirred for 0.5-1 h. The suspension was filtered off at 5 °C and the resulting solid was oven dried. The results are gathered in Table 3.

Table 3

PA: isopropanol; ACN: acetonitrile; THF: tetrahydrofuran.

¹H NMR (200 MHz, CDCh) 6 8.78 (br s, 2H), 7.65 - 7.25 (m, 9H), 7.10 - 6.99 (m, 1 H), 6.62 (q, J = 6.2 Hz, 2H), 4.81 - 4.19 (m*, 1 H), 3.84 - 3.60 (m, 2H), 3.75 (s, 3H), 3.57 - 3.36 (m, 1 H), 3.23 - 2.81 (m, 6H), 2.58 - 2.21 (m, 2H), 2.16 - 1 .68 (m, 6H), 0.94 (t, J = 7.3 Hz, 3H). *The multiplet comprises 2 signals of amide rotamers.

Claims

1. A process for the preparation of optically active secondary amines, or a pharmaceutically or veterinary acceptable salt thereof, compounds of formula (IV),

wherein R¹ is H, C1-C4 alkyl; and R² is C1-C4 alkyl, which comprises the optical resolution of compound of formula (I)

wherein R¹ and R² is as defined above, with (2-naphthoyl)-L-proline, compound of formula (ll-b)

in the presence of a solvent or a mixture of solvents.

2. The process according to claim 1 , wherein R¹ is methyl and R² is n-propyl.

3. The process according to claims 1 and 2, wherein the solvent or a mixture of solvents comprises an organic solvent and water.

4. The process according to claim 3, wherein the organic solvent is selected from acetonitrile, acetone, ethanol, isopropanol, and tetra hydrofuran.

5. The process according to any one of claims 1 to 4, wherein the solvent is a mixture of acetonitrile and water.

6. The process according to any one of claims 3 to 5, wherein the mixture of organic solvent and water is from 15:1 (v/v) to 5:1 (v/v), preferably from 10:1 (v/v) to 7:1 (v/v), more preferably is 8:1 (v/v).

7. The process according to any one of claims 3 to 6, wherein the molar ratio of (2- naphthoyl)-L-proline (compound (ll-b)) to compound of formula (I), wherein R¹ is H, Ci- 04 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R² is n-propyl, is from 0.5 to 1.2 equivalents, preferably from 0.6 to 1.0 equivalents.

8. The process according to any one of claims 1 to 7, wherein the optical resolution is carried out at a temperature from 20 °C to 100 °C, preferably from 50 °C to 85 °C.

9. The process according to any one of claims 1 to 8, wherein the precipitated salt of the amine (I) and the (2-naphthoyl)-L-proline is isolated and neutralised with a base to provide compound (IV).

10. The process according to any one of claims 1 to 9, further comprising dealkylation the group -OR¹ of compound of formula (IV), wherein R¹ is C1-C4 alkyl, preferably R¹ is methyl, and R² is C1-C4 alkyl, preferably R² is n-propyl,

in the presence of hydrobromic acid to provide the corresponding hydrobromide salt of compound of formula (V), wherein R¹ is H and R² is C1-C4 alkyl, preferably R² is n-propyl.

11. The process according to any one of claims 1 to 10, wherein salt compound (V) HBr is neutralized with a base to provide compound of formula (V), wherein R² is C1-C4 alkyl, preferably R² is n-propyl.

12. The process according to any one of claims 1 to 11 , further comprising treating the compound (V) wherein R² is C1-C4 alkyl, preferably R² is n-propyl with a hydride source, preferably sodium borohydride, and 2-(thiophen-2-yl)acetic acid to provide rotigotine.

13. The process according to any one of claims 1 to 12, wherein the rotigotine is treated with an acceptable pharmaceutically or veterinary acceptable acid to provide the corresponding pharmaceutically acceptable or veterinary acceptable salt.

14. The process according to claim 13, wherein the pharmaceutically or veterinary acceptable acid is hydrochloric acid to provide rotigotine hydrochloride.

15. The process according to any one of claims 1 to 14, wherein the pharmaceutically or veterinary acceptable salt of rotigotine is treated with a base to provide rotigotine base.

16. (S)-5-methoxy-/V-propyl-1 ,2,3,4-tetrahydronaphthalen-2-amine, (2-naphthoyl)-L- prolinate salt, compound of formula (lll-b).

(Ill-b)

17. Use of the diastereomeric salt (lll-b) as defined in claim 16, as an intermediate in the preparation of (6S)-(-)-5, 6, 7, 8-tetrahydro-6-[/V-propyl-(2-thienyl)ethyl]amino-1 -naphthol (rotigotine), or a pharmaceutically or veterinary acceptable salt thereof.

18. Use of the optically active compound of formula (IV-a), wherein R¹ is methyl and R² is n-propyl, obtainable by the process according to claims 1 to 8, or an optically active compound of formula (V-a) wherein R¹ is H and R² is n-propyl, obtainable by the process according to claims 9 and 10, as intermediates in the preparation of (6S)-(-)-5, 6,7,8- tetrahydro-6-[/V-propyl-(2-thienyl)ethyl]amino-1 -naphthol (rotigotine), or a pharmaceutically or veterinary acceptable salt thereof.

19. A process for the preparation of (2-naphthoyl)-L-proline, compound of formula (ll-b) comprising:

a) reacting L-proline with compound of formula (VIII)

wherein G is OH, Cl, Br, in the presence of a solvent, and optionally in the presence of an inorganic base. b) isolating (2-naphthoyl)-L-proline, and optionally drying (2-naphthoyl)-L-proline thus obtained.

20. The process according to claim 19, wherein the solvent is an (C6-C14) aromatic hydrocarbon solvent selected from toluene, o-xylene, m-xylene and p-xylene and mixtures thereof.

21. The process according to claims 19 and 20, wherein the isolated (2-naphthoyl)-L- proline (ll-b) is further dissolved or suspended in an ester solvent selected from ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and ethyl malonate.

22. The process according to any one of claims 19 to 21 , wherein the process comprises a previous step of treating 2-naphthoic acid with a chlorinating agent to provide compound (VIII) wherein G is Cl.

23. Use of the (2-naphthoyl)-L-proline, compound of formula (ll-b), as chiral resolving agent of secondary amines of formula (I),

wherein R¹ is H, C1-C4 alkyl, preferably R¹ is methyl; and R² is C1-C4 alkyl, preferably R² is n-propyl.

24. A process for the preparation of (6S)-(-)-5,6,7,8-tetrahydro-6-[N-propyl-(2- thienyl)ethyl]amino-1 -naphthol (rotigotine), or a pharmaceutically or veterinary acceptable salt thereof, the process comprising the optical resolution of compound of formula (I)

wherein R¹ is H, C1-C4 alkyl, preferably R¹ is methyl; and R² is n-propyl, with (2- naphthoyl)-L-proline, compound of formula (lib)

in the presence of a solvent or a mixture of solvents.

25. The process according to claim 24, wherein the solvent or a mixture of solvents comprises an organic solvent and water, wherein the organic solvent is selected from acetonitrile, acetone, ethanol, isopropanol, and tetra hydrofuran.

26. The process according to claims 24 and 25, wherein the solvent is a mixture of acetonitrile and water.

27. The process according to any one of claims 24 to 26, wherein the mixture of organic solvent and water is from 15:1 (v/v) to 5:1 (v/v), preferably from 10:1 (v/v) to 7:1 (v/v), more preferably is 8:1 (v/v).

28. The process according to any one of claims 24 to 27, wherein the molar ratio of (2- naphthoyl)-L-proline (compound (ll-b)) to compound of formula (I), wherein R¹ is H, Ci- 04 alkyl, preferably R¹ is methyl; and R² is n-propyl, is from 0.5 to 1.2 equivalents, preferably from 0.6 to 1.0 equivalents.

29. The process according to any one of claims 24 to 28, wherein the optical resolution is carried out at a temperature from 20 °C to 90 °C, preferably from 25 °C to 75 °C.

30. The process according to any one of claims 24 to 29, wherein the precipitated salt of formula (lll-b) is isolated and neutralised with a base to provide compound (IV-a).

31. The process according to any one of claims 24 to 30, further comprising demethylation the group -OR¹ of compound of formula (IV), wherein R¹ is C1-C4 alkyl, preferably R¹ is methyl and R² is n-propyl,

H

N._R2

OR¹

in the presence of hydrobromic acid to provide the corresponding hydrobromide salt of compound of formula (V-a), wherein R¹ is H and R² is n-propyl.

32. The process according to any one of claims 24 to 31 , wherein salt compound (V- a) HBr is neutralized with a base to provide compound of formula (V-a), wherein R¹ is H and R² is n-propyl.

33. The process according to any one of claims 24 to 32, further comprising treating the compound (V-a), wherein R¹ is H and R² is n-propyl, with a hydride source, preferably sodium borohydride, and 2-(thiophen-2-yl)acetic acid to provide rotigotine.

34. The process according to any one of claims 24 to 33, wherein rotigotine is crystallized by a process comprising: a) dissolving rotigotine in a solvent or a mixture of solvents, preferably a ketone solvent such as acetone, b) adding an antisolvent such as water to facilitate the precipitation, c) optionally, washing the crystals of rotigotine, and d) isolating rotigotine and, e) optionally drying.

35. The process according to any one of claims 24 to 34, wherein the polymorph of rotigotine is the polymorphic form II.

36. The process according to claim 35, wherein rotigotine is micronized.