Preparation process of optically active secondary amines and their use as intermediates

Abstract

The present invention relates to an improved process for preparing optically active secondary amines or pharmaceutically or veterinarily acceptable salts thereof, comprising (2-naphthoyl)-L-proline as a chiral resolving agent, in high yield and high purity. The present invention also relates to a secondary amine, preferably of formula (I) (wherein R 1 is H, C1-C4 alkyl, preferably R 1 is methyl, and R 2 is a C1-C4 alkyl group, preferably R 2 The present invention relates to the use of (2-naphthoyl)-L-proline as a chiral resolving agent for amine compounds (where n-propyl is present), and to its use for the preparation of the resulting optical amine compound of formula (IV) for rotigotine. [Formula 1] JPEG2026521027000032.jpg39153

Description

Technical Field

[0001] The present invention relates to an improved process for preparing an optically active secondary amine or a pharmaceutically or veterinarily acceptable salt thereof in high yield and high purity, comprising (2-naphthoyl)-L-proline as a chiral resolving agent. The present invention also relates to the use of (2-naphthoyl)-L-proline as a chiral resolving agent for an amine compound of secondary amine, preferably of formula (I) (wherein R 1 is H, C1-C4 alkyl, preferably R 1 is methyl, R 2 is C1-C4 alkyl, preferably R 2 is n-propyl), and the use for the preparation of rotigotine of an optically amine compound of formula (IV).

Chemical Formula

Background Art

[0002] Secondary N-alkyl-5-alkoxy-1,2,3,4-tetrahydronaphthalen-2-amine and N-alkyl-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-amine of formula (I) and formula (IV) are described in the art as useful intermediates in the preparation of pharmaceutically active ingredients such as rotigotine.

[0003] Rotigotine, namely (6S)-6-{N-propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8-tetrahydro-1-naphthalenol, is a compound of formula (VII) and is a non-ergoline dopamine agonist for treating the signs and symptoms of Parkinson's disease and restless legs syndrome.

Chemical Formula

[0004] Rotigotine is approved under the brand name Neupro as a transdermal system (patch) in six strengths, delivering nominal doses of 1 mg, 2 mg, 3 mg, 4 mg, 6 mg, and 8 mg per 24 hours, respectively.

[0005] International Publication No. 90 / 13294A1 discloses the resolution of the (+) and (-) isomers of 2-(N-propylamino)-5-methoxytetraline (a secondary amine of formula (I)) using 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 a purification step that increases the cost of the optical resolution of the acid and subsequent processes.

[0006] International Publication No. 91 / 01957A1 discloses a process for resolving racemic 2-(N-propylamino)-5-methoxytetraline, comprising treating it in a hot organic solvent with chiral dialoyl tartaric acid, for example, chiral dialoyl tartaric acid where the chiral dialoyl tartaric acid is dibenzoyl-(-)-tartaric acid or dialoyl tartaric acid is dibenzoyl-(+)-tartaric acid, to form a salt of the amine and chiral dialoyl tartaric acid soluble in the hot solvent, cooling to precipitate the salt, and isolating it. According to Example I, using 0.98 equivalents of chiral dialoyl tartaric acid, a 27.5% yield of the corresponding salt was obtained after two recrystallization steps. By replicating this method, the corresponding diastereomer salt precipitated as a “paste” that was difficult to filter.

[0007] International Publication No. 2010 / 043571A1 discloses a process for resolving racemic 2-(N-propylamino)-5-methoxytetraline using N-(3,5-dinitrobenzoyl)-α-phenylglycine. According to Example 1, an enantiomer ratio of 83:17 is obtained for the corresponding salt in 38% yield. After three recrystallizations, the yield decreases to 15%, and the enantiomer excess ratio becomes 99.5%. Furthermore, the use of dinitro derivatives such as N-(3,5-dinitrobenzoyl)-α-phenylglycine should be avoided on an industrial scale for safety reasons.

[0008] Therefore, an efficient and robust process is needed for the optical resolution of secondary amines of formula (I) in high yield and with high chemical and enantiomer purity. [Overview of the Initiative]

[0009] The inventors of this invention have found formula (I) (wherein R 1 is H, C1-C4 alkyl, preferably R 1 is methyl, and R 2 is a C1-C4 alkyl group, preferably R 2 A racemic compound of (where is n-propyl) was treated with a derivative of L-proline as a resolving agent (see compounds (II-a), (II-b), (II-c), (II-d), and (II-e) in Scheme 1). [ka]

[0010] However, the diastereomeric salts in solid form were obtained only with (2-naphthoyl)-L-proline (II-b) and biphenyl-L-proline (II-a) after several attempts and testing different conditions and solvents. The inventors have surprisingly found that a higher balance between the yield and the enantiomeric excess is obtained using (2-naphthoyl)-L-proline (II-b) as a chiral resolving agent compared to biphenyl-L-proline (II-a) or compared to known prior art resolving agents such as dibenzoyl-(+ / -)-tartaric acid or (+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine.

[0011] Advantageously, (2-naphthoyl)-L-proline (II-b) resolves the secondary amines of formula (I) (where R 1 is H, C1-C4 alkyl, preferably R 1 is methyl, R 2 is C1-C4 alkyl, preferably R 2 is n-propyl) in high yield and high enantiomeric excess without the need for a subsequent recrystallization step that would increase the cost of the overall industrial process. When the compound of formula (I) (where R 2 is n-propyl) is resolved using the compound of formula (II-b), the enantiomerically enriched compound of formula (I) can be advantageously used to prepare rotigotine (the compound of formula (VII)) in high yield and high enantiomeric excess.

[0012] Thus, a first aspect of the present invention is a process for preparing an optically active secondary amine of formula (IV)

Chemical formula

[0013] The above process is shown in Scheme 2. [ka]

[0014] A second aspect of the present invention relates to a compound of formula (III), particularly formula (III-b) (wherein R 1 is methyl, and R 2 This refers to the (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt of the compound (where n is n-propyl). [ka]

[0015] A third aspect of the present invention relates to the use of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt of the compound of formula (III-b) for the preparation of (6S)-(-)-5,6,7,8-tetrahydro-6-[N-propyl-(2-thienyl)ethyl]amino-1-naphthol (rotigotine) or a pharmaceutically or veterinarily acceptable salt thereof.

[0016] A fourth aspect of the present invention relates to a method for preparing rotigotine or a pharmaceutically or veterinarily acceptable salt thereof, using formula (IV-a) (wherein R 1 is methyl, and R 2A compound of (where R is n-propyl), or compound (Va) (wherein R is n-propyl) 1 H is R 2 This refers to the use of (where n-propyl is present).

[0017] A fifth aspect of the present invention refers to a process for preparing (2-naphthoyl)-L-proline (a compound of formula (II-b)).

[0018] A sixth aspect of the present invention is formula (I) (wherein R 1 is H, C1-C4 alkyl, preferably R 1 is methyl, and R 2 is a C1-C4 alkyl group, preferably R 2 This refers to the use of (2-naphthoyl)-L-proline (a compound of formula (II-b)) as a chiral resolving agent for secondary amines (where n is n-propyl). [ka]

[0019] A seventh aspect of the present invention relates to the presence of a solvent or a mixture of solvents, and formula (I) (wherein R 1 is methyl, and R 2 This refers to the preparation process of rotigotine or a pharmaceutically or veterinarily acceptable salt thereof, comprising the optical resolution of a compound of formula (IIb) at (2-naphthoyl)-L-proline (where n is n-propyl).

[0020] definition When describing the compounds and methods of the present invention, the following terms have the following meanings unless otherwise specified.

[0021] As used herein, “alkyl” means a non-unsaturated straight-chain or branched hydrocarbon chain radical having 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.

[0022] As used herein, the term “approximately” typically refers to a statistically significant range of values ​​within 10%. Such a range may be within the typical experimental error of the standard method used to measure and / or determine 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.

[0023] As used herein, the term “organic solvent” refers to an organic molecule capable of at least partially dissolving another substance (i.e., a solute). An organic solvent may be a liquid at room temperature. Suitable organic solvents also include hydrocarbon solvents, preferably aromatic hydrocarbon solvents (C1-C1). 12 )Hydroxide solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oil, etc.), preferably (C6~C 14 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 (C1-C 12 ) Ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, anisole, etc.), amine solvents (e.g., propylamine, diethylamine, triethylamine, aniline, pyridine), alcohol solvents, preferably (C1~C 12The organic solvent may be, but is not limited to, alcoholic 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, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc.), acidic solvents (e.g., acetic acid, hexanoic acid, etc.), carbon disulfide, nitrobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, and acetonitrile. In some embodiments, the organic solvent may be formed by a combination of two or more organic solvents.

[0024] The term "alcohol" refers to a hydrocarbon derivative in which one or more hydrogen atoms are replaced by a known -OH group as a hydroxyl group. Suitable alcohols for the present invention include linear, cyclic, or branched C1-C6 alkyl alcohols and any mixture thereof. Commercially available alcohols are also included. Examples of alcohols include methanol, ethanol, isopropanol, 1-propanol, and 1-butanol.

[0025] As used herein, the term “solvent extraction” refers to the process of separating components of a mixture by using a solvent that has a greater affinity for one component and is therefore capable of separating that component from at least a second component that is less miscible with respect to the solvent than the first component.

[0026] The term "filtration" refers to the process of removing solid particles larger than a certain size from a feed containing a mixture of solid particles and liquid. The term "filtrate" refers to the mixture remaining after the solid particles removed by the filtration process have been removed. It should be understood that this mixture may contain solid particles smaller than a certain particle size. The term "filtration cake" refers to the residual solid material remaining on the feed side of the filtration element.

[0027] The term "evaporation" refers to the change of state of a solvent from liquid to gas and the removal of that gas from the reactor. Various solvents can be evaporated during the synthetic routes disclosed herein. As is known to those skilled in the art, each solvent may have a different evaporation time and / or temperature.

[0028] The term "phase separation" refers to a solution or mixture that has at least two physically distinct regions.

[0029] The term "crystallization" refers to any method known to those skilled in the art, such as crystallization from a single solvent or combination of solvents, by dissolving a compound, sometimes at a high temperature, and precipitating the compound by cooling the solution, removing the solvent from the solution, or both. It further includes methods such as dissolving a compound in a solvent and precipitating it by adding a "poor solvent" (i.e., a solvent in which the desired compound has low solubility or insolubility and which can be used to precipitate such a compound by adding it to a solution in which the compound is dissolved).

[0030] As used herein, the terms “conventional isolation techniques” or “purification” refer to processes that allow a product to be free of foreign elements, thereby yielding a purified product. The term “industrial purification” refers to purification that can be carried out on an industrial scale, such as solvent extraction, filtration, slurrying, washing, phase separation, distillation, centrifugation, or crystallization.

[0031] The term "pharmaceutically or veterinarily acceptable salt" refers to a salt prepared from an acid that is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmacochemically acceptable inorganic or organic acids. Suitable inorganic acids are selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Suitable organic acids are 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, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxymethanesulfonic acid, hydroxyethanesulfonic acid, p-toluenesulfonic acid, and naphthalene-1,5-disulfonic acid.

[0032] The term "micronization" refers to the process of reducing the average diameter of particles in a solid material. Typically, the term micronization is used when the resulting particles have a diameter of only a few micrometers (typically less than 10 μm). Conventional micronization techniques are based on the use of friction to reduce particle size. Such methods include grinding and abrasion. Particle size reduction can also occur as a result of collisions and impacts between particles.

[0033] Embodiments of the present invention are illustrated by the following drawings. [Brief explanation of the drawing]

[0034] [Figure 1] A representative 1H-RMN plot of the (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt (III-b) obtained in Example 4 is shown. [Figure 2] The typical 1H-RMN plot of the (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (biphenyl)-L-proline salt obtained in item 4 of Comparative Example 1 is shown. [Figure 3]A representative thermogravimetric analysis (TGA) plot of the (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt obtained in Example 4 is shown. [Figure 4] Typical differential scanning calorimetry (DSC) results for the (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-prolinate salt obtained in Example 4 are shown. [Figure 5] The typical infrared absorption spectrum (IR) of the (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt obtained in Example 4 is shown. [Modes for carrying out the invention]

[0035] According to the first aspect, formula (I) (wherein R 1 is H, C1-C4 alkyl, preferably R 1 is methyl, and R 2 is a C1-C4 alkyl group, preferably R 2 The molar ratio of (2-naphthoyl)-L-proline (compound (II-b)) to the compound (where n-propyl) may be 0.5 to 1.2 equivalents, preferably 0.6 to 1.0 equivalents, more preferably 0.7 to 0.9 equivalents, and even more preferably about 0.7 equivalents.

[0036] In a particular embodiment, formula (I) (wherein R 1 is methyl, and R 2Racemic 2-(N-propylamino)-5-methoxytetraline compounds (where n-propyl) can be prepared according to Method II, Step 1 of the Prior Art U.S. Patent No. 4,564,628A. In certain embodiments, the hydrochloride salt of 2-(N-propylamino)-5-methoxytetraline is used and neutralized with a base such as an inorganic base (e.g., alkali metal carbonate) in an organic solvent selected from a suitable solvent, preferably a hydrocarbon solvent such as toluene or an ether solvent such as tetrahydrofuran and 2-methyltetrahydrofuran. In certain embodiments, the hydrochloride salt of 2-(N-propylamino)-5-methoxytetraline is neutralized with potassium carbonate in toluene, preferably at 50-60°C, to obtain a solution, after which 2-(N-propylamino)-5-methoxytetraline is extracted.

[0037] In a particular embodiment, formula (III) (wherein R 1 is H, C1-C4 alkyl, preferably R 1 is methyl, and R 2 R2 is a C1-C4 alkyl group, preferably R2 is n-propyl, and more preferably R 1 is methyl, and R 2 The molar ratio of the compound (2-naphthoyl)-L-proline (formula (II-b)) to the compound (where n-propyl) is 0.6 to 1.0 equivalents, preferably 0.7 to 0.9 equivalents.

[0038] In certain embodiments, the solvent may be a mixture of an organic solvent and water, preferably water and a water-miscible organic solvent. Suitable organic solvents may be selected from alcohol solvents, ketone solvents, ether solvents, 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.

[0039] In certain embodiments, the mixture of the organic solvent and water is 15:1v / v to 5:1v / v, preferably 10:1v / v to 7:1v / v, and more preferably about 8:1v / v.

[0040] In certain embodiments, the solvent of the first embodiment is a mixture of acetonitrile and water in a ratio of approximately 8:1 v / v.

[0041] In certain embodiments, the temperature of the first embodiment is 25°C to 100°C, preferably 20°C to 100°C, preferably 50°C to 85°C, more preferably about 80°C, to obtain the solution. In certain embodiments, the obtained solution can be cooled to about 70°C at a cooling rate of about 5°C / 10 mins. In certain embodiments, the obtained solution can be seeded with the corresponding diastereomer salt to promote nucleation. In certain embodiments, the obtained mixture may be cooled to about 25°C, about 20°C, about 15°C, about 10°C, about 5°C, and about 0°C to allow precipitation of the corresponding diastereomer salt. In certain embodiments, the corresponding diastereomer salt can be isolated by conventional isolation techniques and / or purified by crystallization.

[0042] Advantageously, the optical resolution process of the first embodiment, comprising (2-naphthoyl)-L-proline (a compound of formula (II-b)) as a chiral resolving agent, is based on formula (III) (wherein R 1 is H, C1-C4 alkyl, preferably R 1 is methyl, and R 2 is a C1-C4 alkyl group, preferably R 2 The corresponding diastereomer salt of the compound (where is n-propyl) is obtained, and in the first crystallization, the ratio of S / R enantiomers is 95:5 or higher, preferably 97:3 or higher, more preferably 98:2 or higher, and even more preferably 99:1 or higher.

[0043] According to a second aspect of the present invention, formula (III-b) (wherein R 1 is methyl, and R 2The (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt of the compound (where n-propyl) crystallizes with high chemical purity and has an S / R enantiomer ratio of 95:5 or higher, preferably 97:3 or higher, more preferably 98:2 or higher, and even more preferably 99:1 or higher in the first crystallization. [ka]

[0044] In a particular embodiment, formula (III) (wherein R 1 is H, C1-C4 alkyl, preferably R 1 is methyl, and R 2 is a C1-C4 alkyl group, preferably R 2 Diastereomer salts of the compound (where is n-propyl), more preferably (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt of the compound of formula (III-b), can be recrystallized in a suitable solvent. In certain embodiments, the solvent may be a mixture of solvents including an organic solvent and water. Suitable organic solvents may be selected from alcohol solvents, ketone solvents, ether solvents 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 organic solvent and water is 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 of about 6:1 (v / v). In certain embodiments, the organic solvent is a mixture of acetonitrile and water in a ratio of about 8:1 (v / v).

[0045] In certain embodiments, the diastereomer salt of the compound of formula (III) does not necessarily need to be dried and can be used in a wet state in subsequent steps. In certain embodiments, the diastereomer salt of the compound of formula (III) can be isolated and dried.

[0046] Another aspect refers to the use of the diastereomer salt of the compound of formula (III-b), (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt, as an intermediate in the preparation of (6S)-(-)-5,6,7,8-tetrahydro-6-[N-propyl-(2-thienyl)ethyl]amino-1-naphthol (rotigotine) or a pharmaceutically or veterinarily acceptable salt thereof.

[0047] In another aspect of the present invention, formula (III-a) (wherein R 1 H is R 2 The (S)-5-hydroxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt of the compound (where n-propyl) crystallizes with high chemical purity and has an S / R enantiomer ratio of 95:5 or higher, preferably 97:3 or higher, more preferably 98:2 or higher, and even more preferably 99:1 or higher in the first crystallization. [ka]

[0048] In certain embodiments, the (S)-5-hydroxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt of the compound of formula (III-a) can be recrystallized in a suitable solvent. Suitable organic solvents can be selected from alcohol solvents, ketone solvents, ether solvents, 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 organic solvent and water is 15:1 (v / v) to 5:1 (v / v). In certain embodiments, the solvent is a mixture of isopropanol and water in a ratio of about 6:1 (v / v).

[0049] Another aspect refers to the use of a diastereomer salt of the compound of formula (III-a) as an intermediate in the preparation of (6S)-(-)-5,6,7,8-tetrahydro-6-[N-propyl-(2-thienyl)ethyl]amino-1-naphthol (rotigotine) or a pharmaceutically or veterinarily acceptable salt thereof.

[0050] In certain embodiments, diastereomer salts of the amine compound of formula (I) and the compound of formula (III) derived from (2-naphthoyl)-L-proline are isolated and neutralized with a base to obtain the compound of formula (IV). Suitable bases may be inorganic bases selected from alkali metal hydroxides, carbonates, and bicarbonates of alkali metals such as sodium or potassium and alkaline earth metals such as calcium or magnesium, as well as mixtures thereof. In certain embodiments, the diastereomer salt of the compound of formula (III) is neutralized with a base such as an inorganic base (e.g., alkali metal carbonate) in a suitable solvent such as toluene or an ether solvent such as tetrahydrofuran and 2-methyltetrahydrofuran to obtain the compound of formula (IV) (wherein R 1 is H, C1-C4 alkyl, preferably R 1 R2 is methyl, and R2 is C1-C4 alkyl, preferably R 2 A compound (where n-propyl) can be obtained.

[0051] In certain embodiments, the precipitated (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt of the compound of formula (IIIa) is isolated and neutralized with a base to obtain compound (IV) (wherein R1 is methyl, R2 is C1-C4 alkyl, preferably R2 is n-propyl).

[0052] In a particular embodiment, formula (IV) (wherein R 1 is a C1-C4 alkyl group, preferably R 1 is methyl, and R 2 is a C1-C4 alkyl group, preferably R 2 A compound of formula (where R1 is n-propyl) can be demethylated in the presence of hydrobromic acid to obtain a hydrobromide salt of the compound of formula (V), where R1 is H and R2 is a C1-C4 alkyl group, preferably R2 is n-propyl. [ka]

[0053] In certain embodiments, optically active rotigotine can be obtained by treating the corresponding hydrobromide salt of a compound of formula (V) (wherein R1 is H, R2 is C1-C4 alkyl, preferably R2 is n-propyl) with a hydride source, preferably sodium borohydride and 2-(thiophen-2-yl)acetic acid.

[0054] In certain embodiments, a diastereomer salt of the compound of formula (III-b) (wherein R1 is methyl and R2 is n-propyl) (Scheme 2) is neutralized with potassium carbonate in toluene, preferably at 50-60°C, to obtain a solution. Subsequently, the compound of formula (IV) (wherein R1 is methyl and R2 is n-propyl) is extracted, and this is further treated with hydrobromic acid to obtain the corresponding hydrobromide salt of the compound of formula (V), wherein R1 is H and R2 is n-propyl, in high purity and high yield.

[0055] In certain embodiments, the corresponding hydrobromide of a compound of formula (Va) (wherein R1 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 obtain rotigotine according to the process disclosed in Method III of European Patent Application Publication No. 0168505A1.

[0056] In certain embodiments, the corresponding hydrobromide of a compound of formula (Va) (wherein R1 is H and R2 is n-propyl) is neutralized with a base such as an inorganic base (e.g., alkali metal carbonate) in an organic solvent selected from a suitable solvent, preferably a hydrocarbon solvent such as toluene or an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, or anisole, and then treated with 2-(thiophen-2-yl)acetic acid in the presence of sodium borohydride in toluene to obtain rotigotine according to the process disclosed in Method III of European Patent Application Publication No. 0168505A1.

[0057] In certain embodiments, rotigotine may be treated with a pharmaceutically acceptable inorganic or organic acid to obtain a corresponding pharmaceutically acceptable or veterinary salt.

[0058] In certain embodiments, rotigotine can 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.

[0059] In certain embodiments, rotigotine base is treated with an inorganic acid, hydrochloric acid, to obtain rotigotine hydrochloride. In certain embodiments, the polymorphs of the obtained rotigotine hydrochloride are polymorphs I, II, III, IV, and V disclosed in the Prior Art International Publication No. 2009 / 053697A1.

[0060] In certain embodiments, a pharmaceutically acceptable or veterinary salt of rotigotine, such as rotigotine hydrochloride, is treated with a base to obtain rotigotine.

[0061] In certain embodiments, rotigotine is a) Dissolve rotigotine in a solvent or a mixture of solvents, preferably a ketone solvent such as acetone. b) Adding a poor solvent such as water to promote precipitation. c) Wash the rotigotine crystals if necessary. d) Isolating rotigotine, and e) Crystallization may be performed by a process that includes drying.

[0062] In certain embodiments, rotigotine is crystallized by either adding a poor solvent such as water to a solution containing rotigotine in a solvent, preferably a ketone solvent such as acetone, or by adding a poor solvent such as water to a solution containing rotigotine in a solvent, preferably a ketone solvent such as acetone.

[0063] In certain embodiments, the polymorph of rotigotine is polymorph II disclosed in International Publication No. 2009 / 068520A1.

[0064] In certain embodiments, the rotigotine base can be micronized to control or reduce its particle size. According to a fifth aspect of the present invention, formula (II-b) [ka] The preparation process for the compound (2-naphthoyl)-L-proline is as follows: a) L-proline is given by formula (VIII). [ka] (In the formula, G is OH, Cl, or Br, preferably G is Cl.) The reaction is carried out in the presence of the compound and a solvent, and possibly in the presence of an inorganic base. b) The process includes isolating (2-naphthoyl)-L-proline (II-b) and optionally drying the obtained (2-naphthoyl)-L-proline.

[0065] A suitable solvent in step (a) is selected from aromatic hydrocarbon solvents, preferably toluene, o-xylene, m-xylene and p-xylene and mixtures thereof (C6~C 14 ) It can be an aromatic hydrocarbon solvent.

[0066] A suitable inorganic base may be an alkali metal hydroxide such as sodium or potassium, preferably used in an aqueous solution.

[0067] In certain embodiments, (2-naphthoyl)-L-proline(II-b) is prepared from a compound of formula (V) (wherein G is Cl) in a mixture of toluene and water in the presence of sodium hydroxide.

[0068] Step (b) is carried out by a method known to those skilled in the art, for example, by filtration or by using a centrifuge. In certain embodiments, the solid (b) may be dried or used in a moist state in the separate steps.

[0069] 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, as this reduces impurities.

[0070] In certain embodiments, the process for preparing (2-naphthoyl)-L-proline of the compound of formula (II-b) includes the step of treating 2-naphthoic acid with a chlorinating agent to produce compound (VIII) (wherein G is Cl).

[0071] In certain embodiments, 2-naphthoic acid is reacted with a chlorinating agent such as thionyl chloride (SOCl2) to obtain a new compound (VIII) (wherein G is Cl), which is then further reacted with L-proline in the presence of a solvent.

[0072] Another embodiment involves (2-naphthoyl)-L-proline, preferably of formula (I), as a chiral resolving agent for secondary amines. [ka] (In the formula, R 1 is H, C1-C4 alkyl, preferably R 1 is methyl, and R 2 is a C1-C4 alkyl group, preferably R 2 is n-propyl, more preferably R 1 is methyl, and R 2 (is n-propyl) Regarding the use of the compound.

[0073] The present invention will be further described below with reference to examples, which should not be construed in any way as limiting the scope of the invention as defined in the claims. Unless otherwise indicated, all percentages are expressed by weight, and temperatures are in Celsius.

[0074] General method The compound of the present invention is prepared using the following method: 1 The findings were characterized by common analytical techniques such as 1H-NMR, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), and high-performance liquid chromatography (HPLC):

[0075] Proton nuclear magnetic resonance ( 1 (H-NMR) Sample preparation: Approximately 2-5 mg of the sample was dissolved in 0.7 mL of deuterated solvent. Data Acquisition: Proton nuclear magnetic resonance analysis was recorded using a Bruker 400 NMR spectrometer equipped with an ATM-equipped 5 mm z-gradient BBO (Broadband Observe) probe and an automated autosampler. Measurement conditions: Samples were analyzed at room temperature.

[0076] Differential Scanning Calorimetry (DSC) Sample preparation: Approximately 1–4 mg of the sample was weighed into a 40 μL aluminum crucible equipped with a pinhole lid (using an MX5 Mettler Toledo microbalance). Data acquisition: DSC analysis was recorded using a Mettler Toledo DSC822e calorimeter. Program used: Data acquisition and evaluation were performed using the STARe software. Measurement conditions: The sample was heated under dry nitrogen (flow rate: 50 mL / min) at 10°C / min from 30 to 300°C.

[0077] Thermogravimetric analysis (TGA) Sample preparation: Approximately 1–4 mg of the sample was weighed into a 40 μL aluminum crucible equipped with a pinhole lid (using an MX5 Mettler Toledo microbalance). Data Acquisition: Thermogravimetric analysis was recorded using a Mettler Toledo TGA / DSC 3+ with a balanced XP1 type sensor. Program Used: Data acquisition and evaluation were performed using the STARe software. Measurement conditions: The sample was heated under dry nitrogen (flow rate: 10 mL / min) at 10°C / min from 30 to 300°C.

[0078] Fourier transform infrared spectroscopy (FTIR) 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 at 4000–650 cm⁻¹. -1 Within a range of 4cm -1 The spectrum was acquired with 32 scans at this resolution.

[0079] HPLC method HPLC method for determining chemical purity Column: Zorbax Rx-C8 Dimensions: 15cm x 0.46mm ID x 5μm Sample preparation: H2O: 2.0 mg / mL in acetonitrile (30:70) Flow rate: 1.4mL / min Wavelength: 210nm Column temperature: 40℃ Injection volume: 5μL Mobile phase A: Add 1 mL of 10 mM KH2PO4 and triethylamine to 1000 mL of water. Adjust the pH to 5.5 ± 0.1 with phosphoric acid. Mobile phase B: Acetonitrile Analysis time: 35.1 minutes Elution: Gradient (Table 1) [Table 1]

[0080] HPLC method for determining the enantiomer purity of (2-naphthoyl)-L-proline (compound II-b) Column: Amylostris (3-chlorophenylcarbamate) immobilized on 3 μm silica gel (CHIRALCEL-ID3) Dimensions: 4.6mm x 250mm x 3μm Sample preparation: 1 mg / mL in methanol Flow rate: 1.2mL / min Wavelength: 225nm Column temperature: 25℃ Injection volume: 5μL Mobile phase: n-hexane:ethanol:methanol:TFA (80:10:10:0.1) Analysis time: 15 minutes

[0081] HPLC method for determining the enantiomer purity of diastereomer salts (compound III) Column: Cellulose tris(3,5-dimethylphenylcarbamate) (CHIRALCEL-OD) coated on 10 μm silica gel. Dimensions: 4.6mm x 250mm x 10μm Sample preparation: 2mg / mL in phase B Flow rate: 0.8mL / min Wavelength: 225nm Column temperature: 35℃ Injection volume: 10μL Mobile phase: n-hexane: A phase: 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 Analysis time: 60 minutes To determine the enantiomer purity of the diastereomer salts (compound III) prepared in Examples 7, 8, and 9, the above HPLC method was modified as follows: Mobile phase: n-hexane: A phase: DEA: TFA (94:6:0.1:0.05) Injection volume: 15μL Sample preparation: 2 mg / mL in methanol Analysis time: 65 minutes

[0082] HPLC method for determining the enantiomer purity of (S)-6-(N-propylamino)-5,6,7,8-tetrahydronaphthalene-1-ol or its salt, preferably hydrobromide. Column: Cellulose tris(3,5-dimethylphenylcarbamate) (CHIRALCEL-OD) coated on 10 μm silica gel. Dimensions: 4.6mm x 250mm x 10μm Sample preparation: 3mg / mL in phase B Flow rate: 1.0mL / min Wavelength: 225nm Column temperature: 25℃ Injection volume: 10μL Mobile phase: n-hexane: A phase: 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 Analysis time: 25 minutes [Examples]

[0083] Example 1: Preparation of (2-naphthoyl)-L-proline (II-b) A stirred solution containing L-proline (50.00 g, 1 equivalent, 434.3 mmol) in water (150 mL) was treated at 25°C with a solution containing sodium hydroxide (34.74 g, 2.0 equivalent, 868.6 mmol) in water (175 mL). Then, a solution containing 2-naphthoyl chloride (82.79 g, 1.0 equivalent, 434.3 mmol) in toluene (125 mL) was added dropwise with vigorous stirring. The two-phase mixture was stirred at 25°C for 1-2 hours. The pH was adjusted to 1-2 using 37% hydrochloric acid (60 mL), and the resulting suspension was stirred at the same temperature for 2 hours. The suspension was filtered off, and the resulting solid was purified under reflux in toluene, filtered off, and dried. Yield: 110.6g (95%) HPLC: 99.4% (S / R enantiomer ratio 99.7:0.3)

[0084] Example 2: Preparation of (2-naphthoyl)-L-proline (II-b) A suspension containing 2-naphthoic acid (100.00 g, 0.58 mol) in toluene (400 mL) and SOCl2 (63.6 mL, 1.5 equivalents, 0.87 mol) was heated at 90°C for 4 hours. Excess SOCl2 was removed by distillation under vacuum, and the resulting residue was co-distilled with toluene (100 mL). The obtained 2-naphthoyl chloride was dissolved in toluene (170 mL) and stored. Next, a stirred solution containing L-proline (66.87 g, 1.0 equivalent, 0.58 mol) in water (230 mL) was treated at 25°C with an aqueous solution of NaOH 20% w / w (190 mL, 2 equivalents, 1.16 mol). Then, the fresh solution of 2-naphthoyl chloride prepared earlier was added dropwise with vigorous stirring. The two-phase mixture was stirred at 25°C for 2 hours. The organic phase was removed by decantation, and the aqueous phase was acidified to pH 2 with HCl 6M at 25°C. The resulting suspension was stirred at the same temperature for 2 hours, filtered, and washed with water and ethyl acetate. The wet cake was purified under reflux in ethyl acetate, filtered, and dried. Yield: 136.13g (87%) HPLC: 99.9% (S / R enantiomer ratio 99.7:0.3)

[0085] Example 3. Preparation of 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride Acetic acid (385.0 mL, 7.9 equivalents, 6.73 mol) was added dropwise at 10°C to a suspension containing NaBH4 (45.08 g, 1.40 equivalents, 1.19 mol) in tetrahydrofuran (1.00 L). The suspension was then stirred at 25°C for 45 minutes and cooled to 10°C. Propylamine (84.0 mL, 1.2 equivalents, 1.02 mol), followed by a solution containing 5-methoxy-3,4-dihydronaphthalene-2(1H)-one (150.00 g, 1 equivalent, 0.85 mol) in tetrahydrofuran (150 mL), was added at 10°C. The reaction mixture was stirred at 25°C for 2 hours. The mixture was then cooled to 10°C, acidified to pH 2 with HCl 6M, and stirred at 10°C for 3 hours. The resulting suspension was filtered and 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 completely dissolved. The layers were separated, the aqueous layer was washed with 2-MeTHF, and the combined organic layer was washed with water. The organic fraction was cooled to 10°C, acidified to pH 2 with HCl 6M, and stirred at 10°C for 3 hours. The resulting suspension was filtered, washed with tetrahydrofuran, and dried. Yield: 179.89g (83% yield) HPLC: 99.9%

[0086] Example 4: Preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt (III-b) A stirred suspension containing racemic 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride (11.8 g, 1 equivalent, 46.0 mmol) in toluene (90 mL) and K2CO3 10% w / w (117 mL, 2.0 equivalents, 92.0 mmol) was heated to 60°C until completely dissolved. The layers were separated, and the aqueous layer was washed with toluene (30 mL). The combined organic layers were concentrated under vacuum and co-distilled with acetonitrile (30 mL). The resulting free base 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine residue was dissolved in acetonitrile (10 mL) and heated to 60°C. Next, a solution containing 2-naphthoyl)-L-proline (8.67 g, 0.7 equivalents, 32.2 mmol; prepared in the same manner as in Example 1) was added dropwise to a mixture of acetonitrile / H2O (30 mL / 5 mL). Then, acetonitrile / H2O (40 mL / 5 mL) was added, and the mixture was heated under reflux until completely dissolved. The solution was slowly cooled to 0-5°C and stirred for 0.5-1 hour. The suspension was filtered off, and the resulting solid was oven-dried. Yield: 7.29g (32%) HPLC: 99.9% (S / R enantiomer ratio 98.6:1.4) Melting point (DSC start): 207.29℃ TGA: Anhydrous unsolvated.

[0087] IR(cm -1 , KBr):2933, 2876, 2828, 1611, 1597, 1588, 1558, 1468, 1435, 1388, 1342, 1254, 1099, 812, 765, 750, 658, 478.

[0088] 1H NMR(400MHz,CDCl3)δ 8.20(br s,2H),7.98(s,1H),7.88-7.23(m,6H),7.04(t,J=7.9Hz,1H),6.59(dd,J=21.0,7.9Hz,2H),4.72-4.22(m*,1H),3.98-3.58(m ,2H),3.79(s,3H),3.53-3.44(m,4.5Hz,1H),3.33-2.66(m,6H),2.63-2.22(m,2H),2.20-1.52(m,6H),0.89(t,J=7.4Hz,3H). *Multiple lines include two signals from the amide rotational isomer.

[0089] The obtained dried solid (6.0 g) was suspended in a heated acetonitrile / H2O mixture and then cooled to 0-5°C. The suspension was filtered off, and the resulting solid was oven-dried. Yield: 4.63g (77%) HPLC: 99.9% (S / R enantiomer ratio 99.97:0.03)

[0090] Example 5. Preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt (III-b) A solution containing (2-naphthoyl)-L-proline (compound (IIb); 0.7-0.9 equivalents) in a mixture of organic solvent and H2O was added dropwise to a solution containing 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine (11.8 g) in organic solvent (10 mL) at a temperature of 60°C to 80°C. The mixture was then heated until completely dissolved. The resulting solution was slowly cooled to 0-5°C and stirred for 0.5-1 hour. The suspension was filtered at 5°C, and the resulting solid was oven-dried. The results are summarized in Table 2. [Table 2]

[0091] Example 6. Preparation of (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalene-1-ol hydrobromide (Va) A stirred suspension containing (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt (III-b) (60 g, 1 equivalent, 0.12 mol; prepared in the same manner as in Example 2) in toluene (240 mL) and K2CO3 10% w / w (0.23 L, 1.5 equivalents, 0.18 mol) was heated to 60°C until completely dissolved. 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 resulting free base (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine (IV-a) residue was dissolved in AcOH (60 mL) and heated to 40°C. Next, 48% w / w HBr (0.11 L, 8.0 equivalents, 0.96 mol) was added dropwise, and the mixture was heated under reflux for 3 to 6 hours. The resulting suspension was cooled to 0 to 5°C and stirred for 0.5 to 1 hour. The suspension was filtered off, and the resulting solid was oven-dried. Yield: 30.76g (88%) HPLC: 99.4%

[0092] Example 7. Preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt (III-b) A stirred suspension containing 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride (17.50 g, 1 equivalent, 68.4 mmol) in 2-MeTHF (70 mL) and K2CO3 20% w / w (60 mL, 1.5 equivalents, 102.6 mmol) was heated to 50°C until completely dissolved. The layers were separated, and the aqueous layer was washed with 2-MeTHF (17 mL). The combined organic layers were concentrated under vacuum and co-distilled with acetonitrile (30 mL). The obtained free base 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine residue was dissolved in acetonitrile (30 mL) and slowly added at 50°C to a solution containing (2-naphthoyl)-L-proline (11.05 g, 0.6 equivalents, 41.1 mmol) in an acetonitrile / H2O mixture (60 mL / 11.3 mL). The resulting suspension was heated under reflux to ensure complete dissolution. The resulting solution was seeded and slowly cooled to 0-5°C with stirring for 1 hour. The suspension was filtered, washed with the cooled acetonitrile / H2O mixture and acetonitrile, and dried. Yield: 10.50g (31% yield) HPLC: 99.8% (S / R enantiomer ratio 99.56:0.44)

[0093] Example 8. Preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt (III-b) A stirred suspension containing 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride (60.00 g, 1 equivalent, 234.6 mmol) in 240 mL of 2-MeTHF and 200 mL of 20% w / w K2CO3 (1.5 equivalents, 351.9 mmol) was heated to 50°C until completely dissolved. The layers were separated, and the aqueous layer was washed with 60 mL of 2-MeTHF. The combined organic layers were concentrated under vacuum and co-distilled with acetonitrile (60 mL). The obtained free base 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine residue was dissolved in acetonitrile (200 mL) and slowly added at 50°C to a solution containing (2-naphthoyl)-L-proline (56.85 g, 0.9 equivalents, 211.1 mmol) in an acetonitrile / H2O mixture (280 mL / 60 mL). The resulting suspension was heated under reflux to ensure complete dissolution. The resulting solution was seeded and slowly cooled to 0-5°C with stirring for 1 hour. The suspension was filtered, washed with the cooled acetonitrile / H2O mixture and acetonitrile, and dried. Yield: 41.66g (36%) HPLC: 99.8% (S / R enantiomer ratio 99.82:0.18)

[0094] Example 9. Preparation of (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt (III-b) A stirred suspension containing 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride (175.00 g, 1 equivalent, 684.0 mmol) in 2-MeTHF (700 mL) and K2CO3 20% w / w (600 mL, 1.5 equivalents, 1.03 mol) was heated to 50°C until completely dissolved. The layers were separated, and the aqueous layer was washed with 2-MeTHF (175 mL). The combined organic layers were concentrated under vacuum and co-distilled with acetonitrile (175 mL). The obtained free base 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine residue was dissolved in acetonitrile (450 mL) and slowly added at 50°C to a solution containing (2-naphthoyl)-L-proline (138.18 g, 0.75 equivalents, 513.1 mmol) in an acetonitrile / H2O mixture (750 mL / 150 mL). The resulting suspension was heated under reflux to ensure complete dissolution. The resulting solution was seeded and slowly cooled to 0-5°C with stirring for 1 hour. The suspension was filtered off, washed with the cooled acetonitrile / H2O mixture and acetonitrile, and dried. Yield: 115.85g (34%) HPLC: 99.8% (S / R enantiomer ratio 99.86:0.14)

[0095] Example 10: Preparation of (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalene-1-ol hydrobromide (Va) A stirred suspension containing (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-prolinate salt (III-b) (75.00 g, 1 equivalent, 0.15 mol) in 2-MeTHF (300 mL) and K2CO3 20% w / w (135 mL, 1.5 equivalents, 0.23 mol) was heated to 50°C until completely dissolved. 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 free base (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine residue was dissolved in acetic acid (60 mL) and heated to 40°C. Next, 48% w / w HBr (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 hour. The suspension was filtered, washed with cold water, and dried. Yield: 38.16g (87% yield) HPLC: 99.4%

[0096] Example 11. Preparation of (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalene-1-ol (rotigotine) A stirred suspension containing (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalene-1-ol hydrobromide (35.00 g, 1 equivalent, 0.12 mol) in 2-MeTHF (140 mL) and K2CO3 10% w / w (170 mL, 1.1 equivalent, 0.13 mol) was heated to 40°C until completely dissolved. 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-tetrahydronaphthalene-1-ol free base.

[0097] In parallel, NaBH4 (15.34 g, 3.25 equivalents, 397.5 mmol) was gradually added at 10°C to a suspension containing thiophene-2-acetic acid (108.7 g, 6.25 equivalents, 0.76 mol) in anisole (175 mL). The mixture was stirred at 10°C for 30 minutes and at 25°C for 30 minutes.

[0098] Next, the solution containing the previously obtained free base (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalene-1-ol was added to anisole (75 mL) as a suspension and heated at 90°C for 4 hours. The reaction mixture was then cooled to 10°C and slowly quenched with water. The mixture was treated with 5% w / w charcoal for 1 hour, filtered, and washed with ethyl acetate. The filtrate was basicized to pH 8 with K2CO3 20% w / w, the layers were separated, and the organic phase was washed with K2CO3 20% w / w. The organic phase was cooled to 0-5°C, seeded, acidified to pH 2 with HCl 3M in ethyl acetate, and stirred at 25°C for 4 hours. The resulting suspension was filtered and washed with ethyl acetate.

[0099] The wet cake was suspended in ethyl acetate (175 mL) and K2CO3 10% w / w (170 mL, 1.1 equivalents, 0.13 mol) and heated at 40°C until completely dissolved. The layers were separated, and the aqueous layer was washed with ethyl acetate. The combined organic layers were concentrated under vacuum.

[0100] The residue was dissolved in acetone (130 mL) at 25°C, seeds were added, and water (400 mL) was added dropwise. The resulting suspension was stirred at 25°C for 4 hours, filtered, washed with water, and dried. Yield: 36.65g (95% yield) HPLC: 99.4% (S / R enantiomer ratio 100:0)

[0101] Example 12. Preparation of (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalene-1-ol (rotigotine) A stirred suspension containing (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-prolinate salt (8.50 g, 1 equivalent, 33.2 mmol) in 2-MeTHF (34 mL) and K2CO3 10% w / w (30 mL, 1.5 equivalents, 50.0 mmol) was heated to 40°C until completely dissolved. 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.

[0102] The free base (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine residue was dissolved in acetic acid (15 mL) and heated to 40°C. Then, 48% w / w HBr (23 mL, 6.0 equivalents, 199 mmol) was added dropwise, and the mixture was heated at 100°C for 16 hours. The reaction mixture was cooled to 25°C, neutralized with 20% w / w NaOH, basicized to pH 10 with 30% w / w K2CO3, and extracted with 2-MeTHF. The combined organic layers were concentrated under vacuum to obtain 5.88 g of a phenol intermediate (86% yield), which was used in the next step without purification.

[0103] The residue was combined with thiophene-2-acetic acid (24.43 g, 6.0 equivalents, 171.8 mmol) and anisole (60 mL). The suspension was cooled to 10°C, and sodium borohydride (3.32 g, 3.0 equivalents, 95.9 mmol) was added gradually. The suspension was stirred at 10°C for 30 minutes, at 25°C for 30 minutes, and at 90°C for 4 hours. The reaction mixture was cooled to 10°C and slowly quenched with water. The mixture was treated with 5% w / w charcoal for 1 hour, filtered, and washed with ethyl acetate. The filtrate was basicized to pH 8 with K2CO3 20% w / w, the layers were separated, and the organic phase was washed with K2CO3 20% w / w. The organic phase was cooled to 0-5°C, seeded, acidified to pH 2 with HCl 3M in ethyl acetate, and stirred at 25°C for 4 hours. The resulting suspension was filtered and washed with ethyl acetate.

[0104] The wet cake was suspended in ethyl acetate (40 mL) and K2CO3 10% w / w (40 mL, 1.1 equivalents, 31.5 mmol) and heated to 40°C until completely dissolved. 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 at 25°C for 4 hours, filtered, washed with water, and dried. Yield: 8.58g (95% yield) HPLC: 99.4% (S / R enantiomer ratio 100:0)

[0105] Comparative Example 1. Preparation of (S)-5-methoxy-Nn-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (biphenyl)-L-proline salt (III-c) A solution containing biphenyl-L-proline (II-a; 0.6 equivalents) in a mixture of organic solvent and H2O was added dropwise to a solution containing 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine (2 g) in organic solvent (3-5 mL) at a temperature of 60°C to 80°C. The mixture was then heated until completely dissolved. The resulting solution was slowly cooled to 0-5°C and stirred for 0.5-1 hour. The suspension was filtered at 5°C, and the resulting solid was oven-dried. The results are summarized in Table 3. [Table 3]

[0106] 1 H NMR(200MHz,CDCl3)δ 8.78(br s,2H),7.65-7.25(m,9H),7.10-6.99(m,1H),6.62(q,J=6.2Hz,2H),4.81-4.19(m*,1H),3.84-3.60(m,2H),3. 75(s,3H),3.57-3.36(m,1H),3.23-2.81(m,6H),2.58-2.21(m,2H),2.16-1.68(m,6H),0.94(t,J=7.3Hz,3H). *Multiple lines include two signals from the amide rotational isomer.

Claims

1. Formula (IV) 【Chemistry 1】 (In the formula, R １ H, C １ ~C ４ It is alkyl, R ２ C １ ~C ４ (It is alkyl.) A process for preparing an optically active secondary amine of a compound or a pharmaceutically or veterinarily acceptable salt thereof, wherein formula (I) 【Chemistry 2】 (In the formula, R １ and R ２ (As defined above) The compound of formula (II-b) 【Transformation 3】 A process comprising optical resolution of the compound (2-naphthoyl)-L-proline in the presence of a solvent or a mixture of solvents.

2. R １ is methyl and R ２ is n-propyl, the process according to claim 1.

3. The process according to claims 1 and 2, wherein the solvent or 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 tetrahydrofuran.

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 the organic solvent and water is 15:1 (v / v) to 5:1 (v / v), preferably 10:1 (v / v) to 7:1 (v / v), more preferably 8:1 (v / v).

7. Formula (I) (wherein, R １ H, C １ ~C ４ It is alkyl, preferably R １ is methyl, R ２ C １ ~C ４ It is alkyl, preferably R ２ The process according to any one of claims 3 to 6, wherein the molar ratio of (2-naphthoyl)-L-proline (compound (II-b)) to the compound (where is n-propyl) is 0.5 to 1.2 equivalents, preferably 0.6 to 1.0 equivalents.

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

9. The process according to any one of claims 1 to 8, comprising isolating the precipitated salts of amine (I) and (2-naphthoyl)-L-proline and neutralizing them with a base to obtain compound (IV).

10. Formula (IV) 【Chemistry 4】 (In the formula, R １ C １ ~C ４ It is alkyl, preferably R １ is methyl, R ２ C １ ~C ４ It is alkyl, preferably R ２ (is n-propyl) The compound group -OR １ Dealkylation in the presence of hydrobromic acid yields formula (V). 【Transformation 5】 (In the formula, R １ H is R ２ C １ ~C ４ It is alkyl, preferably R ２ (is n-propyl) The process according to any one of claims 1 to 9, further comprising obtaining the corresponding hydrobromide salt of the compound.

11. The salt compound (V)·HBr is neutralized with a base to obtain formula (V) (wherein R ２ C １ ~C ４ It is alkyl, preferably R ２ A process according to any one of claims 1 to 10 to obtain a compound (where is n-propyl).

12. Compound (V) (wherein R ２ C １ ~C ４ It is alkyl, preferably R ２ The process according to any one of claims 1 to 11, further comprising treating (where is n-propyl) with a hydride source, preferably sodium borohydride and 2-(thiophen-2-yl)acetic acid, to obtain rotigotine.

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

14. The process according to claim 13, wherein the pharmaceutically or veterinarily acceptable acid is hydrochloric acid, and rotigotine hydrochloride is obtained.

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

16. Formula (III-b) 【Transformation 6】 The (S)-5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalene-2-amine, (2-naphthoyl)-L-proline salt of the compound.

17. Use of the diastereomer salt (III-b) according to claim 16 as an intermediate in the preparation of (6S)-(-)-5,6,7,8-tetrahydro-6-[N-propyl-(2-thienyl)ethyl]amino-1-naphthol (rotigotine) or a pharmaceutically or veterinarily acceptable salt thereof.

18. As an intermediate in the preparation of (6S)-(-)-5,6,7,8-tetrahydro-6-[N-propyl-(2-thienyl)ethyl]amino-1-naphthol (rotigotine) or a pharmaceutically or veterinarily acceptable salt thereof, formula (IV-a) (wherein R, R) can be obtained by the process described in claims 1 to 8. １ is methyl, R ２ An optically active compound of formula (V-a) (wherein R is n-propyl), which can be obtained by the process described in claims 9 and 10. １ H is R ２ Use of optically active compounds (where n-propyl).

19. Formula (II-b) 【Transformation 7】 A process for preparing the compound (2-naphthoyl)-L-proline, a) Formula (VIII) for L-proline 【Transformation 8】 The reaction is carried out with a compound (wherein G is OH, Cl, or Br) in the presence of a solvent, and possibly an inorganic base. b) A process comprising isolating (2-naphthoyl)-L-proline and optionally drying the (2-naphthoyl)-L-proline thus obtained.

20. The solvent is selected from toluene, o-xylene, m-xylene, and p-xylene, and mixtures thereof (C ６ ~C １４ The process according to claim 19, wherein the solvent is an aromatic hydrocarbon solvent.

21. The process according to claims 19 and 20, wherein the isolated (2-naphthoyl)-L-proline (II-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 includes a pre-step of treating 2-naphthoic acid with a chlorinating agent to obtain compound (VIII) (wherein G is Cl).

23. Equation (I) 【Chemistry 9】 (In the formula, R １ H, C １ ~C ４ It is alkyl, preferably R １ is methyl, R ２ C １ ~C ４ It is alkyl, preferably R ２ (is n-propyl) The use of (2-naphthoyl)-L-proline, a compound of formula (II-b), as a chiral resolving agent for secondary amines.

24. A process for preparing (6S)-(-)-5,6,7,8-tetrahydro-6-[N-propyl-(2-thienyl)ethyl]amino-1-naphthol (rotigotine) or a pharmaceutically or veterinarily acceptable salt thereof, wherein the process comprises formula (I) 【Chemistry 10】 (In the formula, R １ H, C １ ~C ４ It is alkyl, preferably R １ is methyl, R ２ (is n-propyl) The compound of formula (IIb) 【Chemistry 11】 A process comprising optical resolution of the compound (2-naphthoyl)-L-proline in the presence of a solvent or a mixture of solvents.

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

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 the organic solvent and water is 15:1 (v / v) to 5:1 (v / v), preferably 10:1 (v / v) to 7:1 (v / v), more preferably 8:1 (v / v).

28. Formula (I) (wherein, R １ H, C １ ~C ４ It is alkyl, preferably R １ is methyl, R ２ The process according to any one of claims 24 to 27, wherein the molar ratio of (2-naphthoyl)-L-proline (compound (II-b)) to the compound (where is n-propyl) is 0.5 to 1.2 equivalents, preferably 0.6 to 1.0 equivalents.

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

30. The process according to any one of claims 24 to 29, comprising isolating the precipitated salt of formula (III-b) and neutralizing it with a base to obtain compound (IV-a).

31. Formula (IV) 【Chemistry 12】 (In the formula, R １ C １ ~C ４ It is alkyl, preferably R １ is methyl, R ２ (is n-propyl) The compound group -OR １ Demethylated in the presence of hydrobromic acid to obtain formula (V-a) 【Chemistry 13】 (In the formula, R １ H is R ２ The process according to any one of claims 24 to 30, further comprising obtaining the corresponding hydrobromide salt of a compound (where is n-propyl).

32. The salt compound (V-a)·HBr is neutralized with a base to obtain formula (V-a) (wherein R １ H is R ２ A process according to any one of claims 24 to 31 to obtain a compound (where is n-propyl).

33. The aforementioned compound (V-a) (wherein R １ H is R ２ The process according to any one of claims 24 to 32, further comprising treating (where is n-propyl) with a hydride source, preferably sodium borohydride and 2-(thiophen-2-yl)acetic acid, to obtain rotigotine.

34. Rotigotine, a) Dissolve rotigotine in a solvent or a mixture of solvents, preferably a ketone solvent such as acetone. b) Adding a poor solvent such as water to promote precipitation. c) Wash the rotigotine crystals if necessary. d) Isolating rotigotine, and e) The process according to any one of claims 24 to 33, wherein crystallization is performed by a process that optionally includes drying.

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

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

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