Rotigotine intermediate as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a rotigotine intermediate as well as a preparation method and application thereof. The rotigotine intermediate has a structure as shown in a formula 1 and / or a pharmaceutically acceptable salt of the rotigotine intermediate: # imgabs0 #. According to the preparation method, synthesis raw materials are cheap and easy to obtain, chiral 2-amino-2-aryl acetate is innovatively used as a starting material, the high-optical-purity rotigotine intermediate is prepared in a chiral induction mode, rotigotine is prepared through the intermediate, reaction conditions are mild, the target compound is high in optical purity, experimental operation is simple and safe, and the method is suitable for industrial production. Environmental pollution is small, and the method is more suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a rotigotine intermediate and a preparation method and application thereof. Background Art

[0002] Parkinson's disease, also often referred to as "Parkinson's paralysis," is a neurodegenerative disease. The main cause is the degeneration and death of dopaminergic neurons in the substantia nigra, which may be related to multiple factors such as genetics, environmental factors, and aging of the nervous system. The symptoms of Parkinson's disease vary, mainly including resting tremor, muscle rigidity, autonomic dysfunction, and mental and cognitive disorders. Drug treatments for Parkinson's disease include monoamine oxidase type B (MAO-B) inhibitors, dopamine receptor (DR) agonists, catechol-O-methyltransferase (COMT) inhibitors, etc. Rotigotine is a non-ergot selective dopamine receptor agonist drug that stimulates dopamine receptors in the body to simulate the function of dopamine to treat Parkinson's disease.

[0003] Rotigotine is a drug developed by Schwarz Biosciences of Germany for early secondary Parkinson's disease and late Parkinson's disease. Its chemical name is (S)-5,6,7,8-tetrahydro-6-(propyl(2-(2-thienyl)ethyl)amino)-1-naphthol, and its trade name is Neupro. Its structural formula is as follows: .

[0004] The currently reported preparation methods of rotigotine generally use 5-methoxy-2-tetralinone as the starting material. According to the different methods of introducing the chiral center, they can be divided into three types: split synthesis, chiral reagent-assisted synthesis, and stereoselective synthesis. Among them, split synthesis has the problems of yield bottleneck and low split yield; the chiral auxiliary agents reported in the literature mainly include L-phenylglycinol, R-α-phenylethylamine, and (S)-tert-butylsulfenamide, which have the main disadvantages of high price and low optical purity of the target product, which requires further purification; stereoselective synthesis is mainly catalyzed by enzymes or using specific stereoselective catalysts, which is costly in large-scale industrial production. Summary of the invention

[0005] In view of the deficiencies in the above-mentioned prior art, the present invention provides a rotigotine intermediate and a preparation method and application thereof. The synthetic raw materials are cheap and readily available, the reaction conditions are mild, the target compound has high optical purity, the experimental operation is simple and safe, the environmental pollution is small, and it is more suitable for industrial production.

[0006] The specific technical solutions are as follows: The first object of the present invention is to provide a rotigotine intermediate having a structure as shown in formula (1) and / or a pharmaceutically acceptable salt thereof:

[0007] Among them, R 1 Selected from C 1- C 6 Alkyl, substituted C 1- C 6 Alkyl or C 3- C 6 The cycloalkyl group is preferably C 1- C 4 alkyl; R 2 is selected from phenyl, substituted phenyl, naphthyl or substituted naphthyl, preferably phenyl; R 3 Selected from hydrogen or C 1- C 3 alkyl.

[0008] Further, R 3 Selected from hydrogen or propyl, the structure is shown in Formula Ⅰ or Formula Ⅱ:

[0009] Among them, R 1 Selected from C 1- C 6 Alkyl, substituted C 1- C 6 Alkyl or C 3- C 6 The cycloalkyl group is preferably C 1- C 4 alkyl; R 2 It is selected from phenyl, substituted phenyl, naphthyl or substituted naphthyl, preferably phenyl.

[0010] The second object of the present invention is to provide a method for preparing the above-mentioned rotigotine intermediate, wherein the method for preparing the compound of the structure shown in Formula I comprises the following steps: 5-methoxy-2-tetralone and chiral 2-amino-2-aryl acetate undergo a reductive amination reaction under the action of a reducing agent to generate a compound of the structure shown in Formula I:

[0011] Among them, R 1 and R 2 As mentioned above.

[0012] Further, the chiral 2-amino-2-aryl acetate is selected from (S)-2-amino-2-phenylacetic acid methyl ester, (S)-2-amino-2-phenylacetic acid ethyl ester, (S)-2-amino-2-phenylacetic acid n-propyl ester, (S)-2-amino-2-phenylacetic acid isopropyl ester or (S)-2-amino-2-phenylacetic acid tert-butyl ester, preferably (S)-2-amino-2-phenylacetic acid ethyl ester.

[0013] Further, the molar ratio of the 5-methoxy-2-tetralinone to the chiral 2-amino-2-aryl acetate is 1:1-5, preferably 1:1-2; the reducing agent is selected from NaBH 4 , NaBH 3 CN、NaBH(OAc) 3 One or two or more of the following, preferably NaBH 3 CN; the molar ratio of 5-methoxy-2-tetralinone to the reducing agent is 1:0.5~4, preferably 1:0.5~1.5; the solvent used in the reductive amination reaction is selected from C 1 -C 4 One or two or more of alkyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, preferably N,N-dimethylformamide; the reaction temperature of the reductive amination reaction is -30~50°C, preferably -10~30°C.

[0014] Furthermore, the method for preparing the compound of the structure shown in formula II comprises the following steps: the compound of the structure shown in formula I undergoes a reductive amination reaction with propionaldehyde under the action of a reducing agent to generate a compound of the structure shown in formula II

[0015] Among them, R 1 and R 2 As mentioned above.

[0016] Furthermore, the molar ratio of the compound of the structure represented by formula I to propionaldehyde is 1:1-5, preferably 1:1-2; the reducing agent is selected from NaBH 4 , NaBH 3 CN、NaBH(OAc) 3 One or two or more of the following, preferably NaBH(OAc) 3 The molar ratio of the compound of formula I to the reducing agent is 1:0.5~4, preferably 1:0.5~2; the solvent used in the reductive amination reaction is selected from C 1 -C 4One or two or more of alkyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, preferably acetonitrile; the reaction temperature of the reductive amination reaction is -30~50°C, preferably 0°C~40°C.

[0017] The third object of the present invention is to provide use of the above rotigotine intermediate in the preparation of rotigotine.

[0018] Furthermore, the preparation method of rotigotine comprises the following steps: Step a, the compound of the structure represented by formula II is subjected to catalytic hydrogenation reaction under the action of a hydrogenating agent to remove phenylacetic acid ester to obtain intermediate III; Step b, intermediate III and raw material V undergo nucleophilic substitution reaction under alkaline conditions to obtain intermediate IV; Step c: intermediate IV is subjected to demethylation reaction to obtain rotigotine:

[0019] Among them, R 1 and R 2 As mentioned above.

[0020] Further, the hydrogenation reagent is selected from palladium / carbon or palladium hydroxide / carbon, preferably palladium hydroxide / carbon; the solvent used in the catalytic hydrogenation reaction is selected from C 1 -C 4 Alkyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetic acid, acetonitrile, N , N - one or more of dimethylformamide; the reaction temperature of the catalytic hydrogenation reaction is 0~50°C; The alkaline reagent used in the nucleophilic substitution reaction is selected from sodium carbonate, potassium carbonate, sodium sulfite, N , N - one or more of diisopropylethylamine, preferably sodium carbonate; the solvent used in the nucleophilic substitution reaction is selected from C 1 -C 4 Alkyl alcohol, water, dimethyl sulfoxide, N -Methylpyrrolidone, toluene, xylene, acetonitrile, N , N -dimethylformamide, N , N - one or more of dimethylacetamide; the reaction temperature of the nucleophilic substitution reaction is 50-140°C; The reagent for the demethylation reaction is selected from aqueous hydrobromic acid solution, boron tribromide or aluminum trichloride, preferably aluminum trichloride; the solvent used in the demethylation reaction is selected from one or two or more of dichloromethane, toluene, xylene and acetonitrile; the reaction temperature of the demethylation reaction is 0-100°C.

[0021] Furthermore, the method for preparing rotigotine further comprises step a': the compound of the structure represented by formula I undergoes a reductive amination reaction with propionaldehyde under the action of a reducing agent to obtain the compound of the structure represented by formula II:

[0022] Among them, R 1 and R 2 As mentioned above.

[0023] Furthermore, the preparation method of rotigotine further comprises step a": 5-methoxy-2-tetralone and chiral 2-amino-2-aryl acetate undergo reductive amination reaction under the action of a reducing agent to generate a compound of the structure shown in formula I:

[0024] Among them, R 1 and R 2 As mentioned above.

[0025] Furthermore, the preparation method of rotigotine comprises the following steps: The compound of the structure shown in formula I with high optical purity can be prepared by a reductive amination reaction of 5-methoxy-2-tetralinone and chiral 2-amino-2-aryl acetate in the presence of a reducing agent; the reducing agent for the reductive amination reaction is selected from NaBH 3 CN, the temperature of the reductive amination reaction is -10-30°C; The compound represented by the structure of formula I reacts with propionaldehyde in the presence of a reducing agent NaBH(OAc) 3 Under the condition of , a reductive amination reaction occurs to prepare a compound with a structure shown in formula II; The compound of the structure shown in formula II undergoes a catalytic hydrogenation reaction under the catalysis of palladium / carbon to remove the aryl acetate to obtain the intermediate III; the solvent for the catalytic hydrogenation reaction is selected from acetic acid; Intermediate III and intermediate V undergo a nucleophilic substitution reaction under alkaline conditions to obtain intermediate IV; the alkaline reagent used in the nucleophilic substitution reaction is selected from sodium carbonate, and the solvent used is selected from water; Intermediate IV undergoes a demethylation reaction to obtain rotigotine; the reagent for the demethylation reaction is selected from aluminum chloride, and the solvent used is selected from toluene: .

[0026] Compared with the prior art, the present invention has the following beneficial effects: The present invention innovatively uses cheap and readily available chiral 2-amino-2-aryl acetate as a starting material, obtains a rotigotine intermediate with high optical purity by chiral induction, and prepares rotigotine via the intermediate. The reaction conditions are mild, the operation is simple, the yield is high, and the three wastes are less, and the method is more suitable for industrial large-scale production.

[0027] The preparation method of the chiral 2-amino-2-aryl acetate, a starting material innovatively used in the present invention, is simple and can be prepared by an esterification reaction between chiral phenylglycine as a raw material and a corresponding alkyl alcohol. DETAILED DESCRIPTION

[0028] The principles and features of the present invention are described below in conjunction with the examples, which are only used to explain the present invention and are not intended to limit the scope of the present invention. It should be understood by those skilled in the art that there are other synthetic routes to form the compounds of the present invention, and the following are non-limiting examples.

[0029] Example 1 Formula I-1: Compound ( S )-2-((( S Preparation of methyl 2-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-phenylacetate hydrochloride:

[0030] In a 250 mL two-necked flask, add 5-methoxy-2-napthalone (17.6 g, 100 mmol, 1.0 eq), ( S )-2-amino-2-phenylacetic acid methyl ester hydrochloride (21.1 g, 105 mmol, 1.05 eq), N , N -dimethylformamide (54.0 g, 3g / g), stirred until the internal temperature reached 5°C, sodium cyanoborohydride (9.4 g, 150 mmol, 1.5 eq) was added in batches, stirred at 5°C for 6 hours, and after the reaction was complete (the ee value of the reaction solution was 99.2%), the reaction was quenched with water. Concentrated under reduced pressure at 55°C to remove part of N,N-dimethylformamide, water and toluene were added for extraction, the liquids were separated, the organic phase was washed once with water, the organic phase was collected, ethyl acetate-HCl solution was added dropwise under stirring to form salt until the pH value was 1, a solid was precipitated, filtered, the filter cake was rinsed with toluene, and dried to obtain 27.7 g of an off-white solid with a yield of 85.1% and an ee value of 100%, i.e., compound Ⅰ-1.

[0031] MS m / z (ESI): 326.19[M+1]. 1H NMR (400 MHz, DMSO- d 6 ) δ 10.03 (d, J = 25.8Hz, 1H), 7.71 (ddd, J = 9.5, 6.8, 2.2 Hz, 2H), 7.48 (qt, J = 5.3, 3.0 Hz, 3H),7.10 (td, J = 7.9, 2.4 Hz, 1H), 6.82-6.58 (m, 2H), 5.54 (s, 1H), 3.73 (dd, J =3.1, 2.1 Hz, 6H), 3.29-2.94 (m, 3H), 2.92 – 2.77 (m, 1H), 2.46-2.29 (m, 1H), 2.08 (s, 2H), 1.90-1.74 (m, 1H). Example 2 Formula I-2: Compound ( S )-2-((( S Preparation of ethyl 2-phenylacetate (5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-phenylacetate hydrochloride:

[0032] In a 500 mL two-necked flask, add 5-methoxy-2-napthalone (50.4 g, 286 mmol, 1.0 eq), ( S )-2-amino-2-phenylacetic acid ethyl ester hydrochloride (64.8 g, 300 mmol, 1.05 eq), N , N -dimethylformamide (150.0 g, 3 g / g), stirred until the internal temperature reached 5°C, began to add sodium cyanoborohydride (26.9 g, 429 mmol, 1.5 eq) in batches, stirred at 5°C for 6 hours, HPLC monitored the reaction after completion (reaction solution ee value 100%), quenched the reaction with water. Concentrated under reduced pressure at 55°C to remove part of N,N-dimethylformamide, added water and toluene for extraction, separated, the organic phase was washed with water once, the organic phase was collected, and ethyl acetate-HCl solution was added dropwise under stirring to form salt until the pH value was 1, solid precipitated, filtered, the filter cake was rinsed with toluene, and dried to obtain 92.7 g of off-white solid, with a yield of 86.2% and an ee value of 100%, i.e., compound Ⅰ-2.

[0033] MS m / z (ESI): 340.21[M+1]. 1H NMR (400 MHz, DMSO- d 6 ) δ 7.45-7.40 (m,2H), 7.38-7.31 (m, 2H), 7.30-7.25 (m, 1H), 7.04 (td, J = 7.9, 1.9 Hz, 1H), 6.70(dt, J = 8.2, 1.3 Hz, 1H), 6.63 (ddd, J = 11.8, 7.6, 1.0 Hz, 1H), 4.60 (dd, J =9.7, 2.9 Hz, 1H), 4.19-3.98 (m, 2H), 3.72 (d, J = 3.3 Hz, 3H), 2.89 (td, J =16.5, 4.3 Hz, 1H), 2.78-2.65 (m, 2H), 2.59-2.52 (m, 2H), 2.45-2.31 (m, 1H), 2.01-1.89 (m, 1H), 1.49 (dddd, J = 15.6, 12.2, 9.7, 5.9 Hz, 1H), 1.11 (td, J =7.1, 2.7 Hz, 3H). Example 3 Formula I-3: Compound ( S )-2-((( S Preparation of 5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-phenylacetic acid isoester hydrochloride:

[0034] In a 100 mL two-necked flask, add 5-methoxy-2-napthalone (5.0 g, 28.4 mmol, 1.0 eq), ( S )-2-amino-2-phenylacetic acid isopropyl ester hydrochloride (6.8 g, 29.8 mmol, 1.05 eq), N , N-dimethylformamide (15.0 g, 3 g / g), stirred until the internal temperature reached 5°C, sodium cyanoborohydride (2.7 g, 42.6 mmol, 1.5 eq) was added in batches, stirred at 5°C for 6 hours, and after the reaction was complete (the ee value of the reaction solution was 98.6%), the reaction was quenched with water. The mixture was concentrated under reduced pressure at 55°C to remove part of the N,N-dimethylformamide, and water and toluene were added for extraction. The organic phase was washed once with water, and the organic phase was collected. Ethyl acetate-HCl solution was added dropwise under stirring to form a salt until the pH value was 1, and a solid was precipitated. The filter cake was washed with toluene and dried to obtain 9.5 g of an off-white solid with a yield of 85.5% and an ee value of 99.2%, i.e., compound Ⅰ-3.

[0035] MS m / z (ESI): 354.25[M+1]. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.84 (s, 1H),7.66 (ddd, J = 10.1, 6.5, 2.1 Hz, 2H), 7.49 (td, J = 5.1, 1.8 Hz, 3H), 7.11 (td, J = 7.9, 2.6 Hz, 1H), 6.77 (dt, J = 8.3, 1.4 Hz, 1H), 6.67 (dd, J = 20.7, 7.7 Hz,1H), 5.56-5.41 (m, 1H), 3.73 (d, J = 5.2 Hz, 2H), 3.27-2.78 (m, 4H), 2.38 (q, J =8.7, 7.9 Hz, 2H), 1.78 (dd, J = 10.8, 5.6 Hz, 1H), 1.24 (t, J = 6.0 Hz, 3H), 1.04(dd, J = 6.2, 3.1 Hz, 3H). Example 4 Formula I-4: Compound ( S )-2-((( S Preparation of 5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-phenylacetic acid n-propyl ester hydrochloride:

[0036] In a 100 mL two-necked flask, add 5-methoxy-2-tetralone (10.0 g, 56.8 mmol, 1.0 eq), ( S )-2-amino-2-phenylacetic acid n-propyl ester hydrochloride (13.6 g, 59.6 mmol, 1.05 eq), N , N -dimethylformamide (30.0 g, 3g / g), stirred until the internal temperature reached 5°C, sodium cyanoborohydride (5.4 g, 85.2 mmol, 1.5eq) was added in batches, stirred at 5°C for 6 hours, and after the reaction was complete (the ee value of the reaction solution was 100%), the reaction was quenched with water. Concentrated under reduced pressure at 55°C to remove part of N,N-dimethylformamide, added water and toluene for extraction, separated, the organic phase was washed with water once, the organic phase was collected, and ethyl acetate-HCl solution was added dropwise under stirring to form salt until the pH value was 1, a solid was precipitated, filtered, the filter cake was rinsed with toluene, and dried to obtain 18.5 g of an off-white solid with a yield of 83.8% and an ee value of 100%, i.e., compound Ⅰ-4.

[0037] MS m / z (ESI): 354.25[M+1]. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.93 (d, J = 25.2Hz, 1H), 7.79-7.60 (m, 2H), 7.45 (dd, J = 6.6, 4.5 Hz, 3H), 7.06 (td, J = 7.9,2.0 Hz, 1H), 6.78-6.70 (m, 1H), 6.63 (dd, J = 21.0, 7.7 Hz, 1H), 5.49 (d, J = 9.7Hz, 1H), 4.08 (tt, J = 6.4, 1.2 Hz, 2H), 3.69 (d, J = 5.1 Hz, 3H), 3.35 (s, 1H), 3.23-2.75 (m, 4H), 2.34 (q, J = 7.2 Hz, 2H), 1.85-1.70 (m, 1H), 1.55-1.41 (m,2H), 0.68 (td, J = 7.4, 1.3 Hz, 3H). Example 5 Formula I-5: Compound (S )-2-((( S Preparation of tert-butyl 5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-phenylacetate hydrochloride:

[0038] In a 250 mL two-necked flask, add 5-methoxy-2-napthalone (25.2 g, 143 mmol, 1.0 eq), ( S )-tert-butyl 2-amino-2-phenylacetate hydrochloride (36.6 g, 150.1 mmol, 1.05 eq), N , N -dimethylformamide (75.6 g, 3g / g), stirred until the internal temperature reached 5°C, sodium cyanoborohydride (13.5 g, 214.5 mmol, 1.5eq) was added in batches, stirred at 5°C for 6 hours, and after the reaction was complete (the ee value of the reaction solution was 98.4%), the reaction was quenched with water. The mixture was concentrated under reduced pressure at 55°C to remove part of the N,N-dimethylformamide, and water and toluene were added for extraction. The organic phase was washed once with water, and the organic phase was collected. Ethyl acetate-HCl solution was added dropwise under stirring to form a salt until the pH value was 1, and a solid was precipitated. The filter cake was washed with toluene and dried to obtain 50.3 g of an off-white solid with a yield of 87.1% and an ee value of 99.0%, i.e., compound Ⅰ-5.

[0039] MS m / z (ESI): 404.91[M+1]. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.72-7.63 (m,2H), 7.54-7.42 (m, 2H), 7.28-7.13 (m, 1H), 7.10 (td, J = 7.9, 2.4 Hz, 1H), 6.75(dd, J = 8.2, 2.5 Hz, 1H), 6.66 (dd, J = 20.4, 7.7 Hz, 1H), 5.34 (d, J = 17.3 Hz,1H), 3.73 (d, J = 5.1 Hz, 3H), 3.25-2.77 (m, 4H), 2.44-2.30 (m, 2H), 1.80 (dq, J = 11.9, 6.6, 6.2 Hz, 1H), 1.37 (s, 10H). Example 6 Formula II-1: Compound ( S )-2-((( S Preparation of methyl 2-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(n-propyl)amino)-2-phenylacetate:

[0040] In a 500 mL two-necked flask, compound Ⅰ-1 (27.5 g, 76 mmol, 1.0 eq), acetonitrile (110 g, 4 g / g), propionaldehyde (7.9 g, 137 mmol, 1.8 eq) were added, stirred until dissolved, cooled to 5 degrees Celsius, sodium triacetoxyborohydride (32.2 g, 152 mmol, 2.0 eq) was added, and the reaction was carried out at 40°C for 5 hours. The reaction was monitored by HPLC. The reaction was cooled, water was added to quench the reaction, concentrated and dried, toluene and water were added to extract the liquid, and the organic phase was extracted once with saturated sodium bicarbonate aqueous solution. The organic phase was collected, concentrated and dried to obtain 27.9 g of a yellow-brown oil, which was compound Ⅱ-1, which was directly used in the next step reaction with a yield of 100%. MS m / z (ESI): 368.41[M+1].

[0041] Example 7 Formula II-2: Compound ( S )-2-((( S Preparation of ethyl (5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(n-propyl)amino)-2-phenylacetate:

[0042] In a 1000 mL two-necked flask, compound Ⅰ-2 (92.1 g, 245 mmol, 1.0 eq), acetonitrile (368 g, 4g / g), propionaldehyde (25.6 g, 441 mmol, 1.8 eq) were added, stirred until dissolved, cooled to 5 degrees Celsius, sodium triacetoxyborohydride (103.8 g, 490 mmol, 2.0 eq) was added, and the reaction was carried out at 40°C for 5 hours. The reaction was monitored by HPLC until the end, cooled, water was added to quench the reaction, concentrated and dried, toluene and water were added to extract the liquid, the organic phase was extracted once with saturated sodium bicarbonate aqueous solution, the organic phase was collected, concentrated and dried to obtain 93.4 g of a yellow-brown oil, which was compound Ⅱ-2, which was directly used in the next step reaction with a yield of 100%, MS m / z (ESI): 382.32[M+1].

[0043] Example 8 Formula II-3: Compound ( S )-2-((( SPreparation of (5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(n-propyl)amino)-2-phenylacetic acid isopropyl ester:

[0044] In a 100 mL two-necked flask, compound Ⅰ-3 (9.2 g, 23.6 mmol, 1.0 eq), acetonitrile (37 g, 4 g / g), propionaldehyde (2.4 g, 42.5 mmol, 1.8 eq) were added, stirred until dissolved, cooled to 5 degrees Celsius, sodium triacetoxyborohydride (10.0 g, 47.2 mmol, 2.0 eq) was added, and the reaction was carried out at 40°C for 5 hours. The reaction was monitored by HPLC. The reaction was cooled, water was added to quench the reaction, concentrated and dried, toluene and water were added to extract the liquid, and the organic phase was extracted once with saturated sodium bicarbonate aqueous solution. The organic phase was collected, concentrated and dried to obtain 9.3 g of a yellow-brown oil, which was compound Ⅱ-3, which was directly used in the next step reaction with a yield of 100%, MS m / z (ESI): 396.22[M+1].

[0045] Example 9 Formula II-4: Compound ( S )-2-((( S Preparation of n-propyl 2-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(n-propyl)amino)-2-phenylacetate:

[0046] In a 100 mL two-necked flask, compound Ⅰ-4 (18.0 g, 46.2 mmol, 1.0 eq), acetonitrile (72 g, 4g / g), propionaldehyde (4.8 g, 83.1 mmol, 1.8 eq) were added, stirred until dissolved, cooled to 5 degrees Celsius, sodium triacetoxyborohydride (19.6 g, 92.3 mmol, 2.0 eq) was added, and the reaction was carried out at 40°C for 5 hours. The reaction was monitored by HPLC until the end, cooled, water was added to quench the reaction, concentrated and dried, toluene and water were added to extract the liquid, the organic phase was extracted once with saturated sodium bicarbonate aqueous solution, the organic phase was collected, concentrated and dried to obtain 18.3 g of a yellow-brown oil, which was compound Ⅱ-4, which was directly used in the next step reaction with a yield of 100%, MS m / z (ESI): 396.22[M+1].

[0047] Example 10 Formula II-5: Compound ( S )-2-((( S Preparation of tert-butyl 2-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(n-propyl)amino)-2-phenylacetate:

[0048] In a 100 mL two-necked flask, compound Ⅰ-5 (50.2 g, 124.2 mmol, 1.0 eq), acetonitrile (201 g, 4g / g), propionaldehyde (13.0 g, 224 mmol, 1.8 eq) were added, stirred until dissolved, cooled to 5 degrees Celsius, sodium triacetoxyborohydride (52.7 g, 248.6 mmol, 2.0 eq) was added, and the reaction was carried out at 40°C for 5 hours. The reaction was monitored by HPLC. The reaction was cooled, water was added to quench the reaction, concentrated and dried, toluene and water were added to extract the liquid, and the organic phase was extracted once with saturated sodium bicarbonate aqueous solution. The organic phase was collected, concentrated and dried to obtain 50.9 g of a yellow-brown oil, which was compound Ⅱ-5, which was directly used in the next step reaction with a yield of 100%. MS m / z (ESI): 410.26[M+1].

[0049] Embodiment 11 Formula III: Compound ( S )-5-methoxy- N Preparation of 1-propyl-1,2,3,4-tetrahydronaphthalene-2-amine hydrochloride:

[0050] In a 500 mL single-mouth round-bottom flask, add the compound of formula II-2 (50 g, 131 mmol, 1.0eq), dissolve it in acetic acid (200 g, 4 g / g), add palladium carbon (2.0 g, 4% w / w), replace it with hydrogen three times, react at 45°C for 10 hours, monitor the completion of the reaction by HPLC, remove the palladium carbon by suction, rinse the filter cake with acetic acid, collect the filtrate, concentrate and spin-dry, add ethanol to dissolve it, add concentrated hydrochloric acid dropwise thereto with stirring, precipitate a solid, adjust the pH to 1, filter, rinse the filter cake with cold ethanol, and dry the filter cake to obtain 32 g of a white solid, which is the compound of formula III. The compound of formula III is prepared from the compound of formula I-2, and the total yield of two steps is 95.5%.

[0051] MS m / z (ESI): 220.18[M+1]. 1 H NMR (400 MHz, Methanol- d 4 ) δ 7.13 (t, J =7.9 Hz, 1H), 6.81-6.71 (m, 2H), 3.81 (s, 3H), 3.47 (tdd, J = 10.9, 5.1, 3.2 Hz,1H), 3.24 (ddd, J= 15.9, 5.1, 2.1 Hz, 1H), 3.14-3.06 (m, 2H), 3.01 (ddd, J =18.0, 5.9, 3.4 Hz, 1H), 2.95-2.83 (m, 1H), 2.65 (ddd, J = 17.6, 11.4, 6.2 Hz,1H), 2.35 (ddtd, J = 12.6, 6.4, 3.2, 2.2 Hz, 1H), 1.88-1.70 (m, 3H), 1.07 (t, J =7.4 Hz, 3H). Example 12 Formula IV: Compound ( S )-5-methoxy- N -propyl- N Preparation of -(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalene-2-amine:

[0052] In a 250 mL single-mouth round-bottom flask, add the compound of formula III (32 g, 125.1 mmol, 1.0 eq), 2-(thiophen-2-yl)ethyl p-toluenesulfonate (56.5 g, 200.2 mmol, 1.6 eq), sodium carbonate (33.2 g, 312.8 mmol, 2.5 eq), water (96 g, 3 g / g), evacuate with nitrogen three times, react at 100°C for 10 hours. After the reaction is completed by HPLC monitoring, toluene and water are added to extract and separate the liquids, the organic phase is collected, the organic phase is washed with water once, the organic phase is spin-dried, methyl tert-butyl ether is added to dissolve, ethyl acetate-HCl is added dropwise under stirring to form a salt, a solid is precipitated, and the filter cake is rinsed with methyl tert-butyl ether and dried to obtain 42.7 g of a white solid, which is the compound of formula IV, with a yield of 93.4%.

[0053] MS m / z (ESI): 330.15[M+1]. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.28 (dd, J = 5.1,1.2 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.92 (dd, J = 5.1, 3.4 Hz, 1H), 6.87 (dt, J= 3.3, 1.0 Hz, 1H), 6.68 (dd, J = 7.9, 1.1 Hz, 2H), 3.73 (s, 3H), 2.93-2.80 (m,4H), 2.80 -2.60 (m, 4H), 2.49-2.36 (m, 3H), 2.00-1.89 (m, 1H), 1.55-1.35 (m,3H), 0.84 (t, J = 7.3 Hz, 3H) Embodiment 13 Formula V: Preparation of Rotigotine:

[0054] In a 250 mL single-mouth round-bottom flask, add the compound of formula IV (10.0 g, 27.3 mmol, 1.0 eq), anhydrous aluminum chloride (10.9 g, 82.0 mmol, 3.0 eq), thiourea (6.2 g, 82.0 mmol, 3.0 eq), and dissolve in toluene (50.0 g, 5 g / g), and react at 70°C for 6 h. After the reaction is completed by HPLC monitoring, the solvent is evaporated under reduced pressure, and water is added dropwise to quench the reaction. The pH value is adjusted to 9 with a saturated sodium carbonate aqueous solution, and dichloromethane is added for extraction, washed with water, and the organic phases are combined and dried by rotation. Ethanol and water are added to cool to about -10°C for recrystallization, and the solid is precipitated, filtered, and the filter cake is rinsed with cold ethanol to obtain 7.8 g of an off-white solid with a yield of 90.3%.

[0055] MS m / z (ESI): 316.14[M+1]. 1 H NMR (400 MHz, Chloroform- d ) δ 11.64 (s,1H), 7.20 (dt, J = 5.0, 1.7 Hz, 1H), 7.02-6.81 (m, 4H), 6.53-6.39 (m, 1H), 3.69-2.92 (m, 9H), 2.84 (dt, J = 17.4, 5.3 Hz, 1H), 2.47-2.17 (m, 2H), 2.13-1.86 (m, 2H), 1.78 (dtd, J = 16.6, 11.7, 5.6 Hz, 1H), 1.03 (td, J = 7.4, 2.6 Hz,3H). The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A rotigotine intermediate, characterized in that: Having the structure shown in Formula 1 and / or its pharmaceutically acceptable salt: Wherein, R1 is selected from C 1- C6 alkyl, substituted C 1- C6 alkyl or C 3- C6 cycloalkyl; R2 is selected from phenyl, substituted phenyl, naphthyl or substituted naphthyl; R3 is selected from hydrogen or C 1- C3 alkyl.

2. The rotigotine intermediate according to claim 1, characterized in that R3 is selected from hydrogen or propyl, and the structure is shown in Formula I or Formula II: Wherein, R1 is selected from C 1- C6 alkyl, substituted C 1- C6 alkyl or C 3- C6 cycloalkyl; R2 is selected from phenyl, substituted phenyl, naphthyl or substituted naphthyl.

3. A method for preparing a rotigotine intermediate as claimed in claim 2, characterized in that: The method for preparing the compound of the structure shown in formula I comprises the following steps: 5-methoxy-2-tetralone and chiral 2-amino-2-aryl acetate undergo reductive amination reaction under the action of a reducing agent to generate the compound of the structure shown in formula I.

4. The method for preparing a rotigotine intermediate according to claim 3, characterized in that: The chiral 2-amino-2-aryl acetate is selected from (S)-2-amino-2-phenylacetic acid methyl ester, (S)-2-amino-2-phenylacetic acid ethyl ester, (S)-2-amino-2-phenylacetic acid n-propyl ester, (S)-2-amino-2-phenylacetic acid isopropyl ester or (S)-2-amino-2-phenylacetic acid tert-butyl ester.

5. The method for preparing a rotigotine intermediate according to claim 3, characterized in that: The molar ratio of the 5-methoxy-2-tetralone to the chiral 2-amino-2-aryl acetate is 1:1-5; the reducing agent is selected from one or two or more of NaBH4, NaBH3CN, and NaBH(OAc)3; the molar ratio of the 5-methoxy-2-tetralone to the reducing agent is 1:0.5-4; the solvent used in the reductive amination reaction is selected from one or two or more of C1-C4 alkyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide; and the reaction temperature of the reductive amination reaction is -30-50°C.

6. The method for preparing a rotigotine intermediate according to claim 3, characterized in that: The method for preparing the compound of the structure shown in formula II comprises the following steps: the compound of the structure shown in formula I and propionaldehyde undergo a reductive amination reaction under the action of a reducing agent to generate a compound of the structure shown in formula II.

7. The method for preparing a rotigotine intermediate according to claim 6, characterized in that: The molar ratio of the compound of the structure shown in formula I to propionaldehyde is 1:1-5; the reducing agent is selected from one or two or more of NaBH4, NaBH3CN, and NaBH(OAc)3; the molar ratio of the compound of the structure shown in formula I to the reducing agent is 1:0.5-4; the solvent used in the reductive amination reaction is selected from one or two or more of C1-C4 alkyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol methyl ether, ethylene glycol dimethyl ether, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide; the reaction temperature of the reductive amination reaction is -30-50°C.

8. Use of the rotigotine intermediate according to claim 1 in the preparation of rotigotine.

9. Use of the rotigotine intermediate according to claim 2 in the preparation of rotigotine.

10. The use according to claim 9, characterized in that: The preparation method of rotigotine comprises the following steps: Step a, the compound of the structure represented by formula II is subjected to catalytic hydrogenation reaction under the action of a hydrogenating agent to remove phenylacetic acid ester to obtain intermediate III; Step b, intermediate III and raw material V undergo nucleophilic substitution reaction under alkaline conditions to obtain intermediate IV; Step c: intermediate IV is subjected to demethylation reaction to obtain rotigotine: 。 11. The use according to claim 10, characterized in that: The hydrogenation reagent is selected from palladium / carbon or palladium hydroxide / carbon; the solvent used in the catalytic hydrogenation reaction is selected from C1-C4 alkyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetic acid, acetonitrile, N , N - one or more of dimethylformamide; the reaction temperature of the catalytic hydrogenation reaction is 0~50°C; The alkaline reagent used in the nucleophilic substitution reaction is selected from sodium carbonate, potassium carbonate, sodium sulfite, N , N - one or more of diisopropylethylamine; the solvent used in the nucleophilic substitution reaction is selected from C1-C4 alkyl alcohol, water, dimethyl sulfoxide, N -Methylpyrrolidone, toluene, xylene, acetonitrile, N , N -dimethylformamide, N , N - one or more of dimethylacetamide; the reaction temperature of the nucleophilic substitution reaction is 50-140°C; The reagent of the demethylation reaction is selected from aqueous hydrobromic acid solution, boron tribromide or aluminum trichloride; the solvent used in the demethylation reaction is selected from one or two or more of dichloromethane, toluene, xylene and acetonitrile; the reaction temperature of the demethylation reaction is 0-100°C.

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