Rotigotine intermediate, its preparation method and application

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a rotigotine intermediate, a preparation method thereof and an application. The rotigotine intermediate has a structure shown in Formula 1 and / or a pharmaceutically acceptable salt thereof:. The preparation method provided by the present invention uses inexpensive and easily available synthetic raw materials, innovatively uses chiral 2-amino-2-aryl acetate as a starting material, and prepares a rotigotine intermediate with high optical purity by means of chiral induction. Rotigotine is prepared from the intermediate, the reaction conditions are mild, the optical purity of the target compound is high, the experimental operation is simple and safe, the environmental pollution is small, and it is more suitable for industrial production.

Description

Technical Field

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

[0002] Parkinson's disease, often also known as "shaking palsy", is a neurodegenerative disease of the nervous system. 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, etc. Drug treatment of Parkinson's disease includes 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, which treats Parkinson's disease by stimulating dopamine receptors in the body and simulating the function of dopamine.

[0003] Rotigotine is a drug developed by Schwarz Biosciences in Germany for early secondary Parkinson's disease and advanced 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] 。

[0005] The preparation methods of rotigotine reported currently generally use 5-methoxy-2-tetralone as the starting material. According to different methods of introducing chiral centers, they can be divided into three types: resolution synthesis, chiral reagent-assisted synthesis and stereoselective synthesis. Among them, resolution synthesis has problems such as a yield bottleneck and low resolution yield; the chiral auxiliaries reported in the current literature mainly include L-phenylglycinol, R-α-phenylethylamine, and (S)-tert-butylsulfinamide, which mainly have disadvantages such as high price and low optical purity of the target product that requires further purification; stereoselective synthesis mainly uses enzyme catalysis or specific stereoselective catalysts, which are costly in large-scale industrial production. Summary of the Invention

[0006] In view of the above deficiencies of the prior art, the present invention provides a rotigotine intermediate, a preparation method thereof and an application thereof. The synthesis raw materials are cheap and easily available, the reaction conditions are mild, the optical purity of the target compound is high, the experimental operation is simple and safe, the environmental pollution is small, and it is more suitable for industrial production.

[0007] The specific technical solutions are as follows:

[0008] The first object of the present invention is to provide a rotigotine intermediate having a structure shown in formula (1) and / or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Wherein, R1 is selected from C 1- C6 alkyl, substituted C 1- C6 alkyl or C 3- C6 cycloalkyl, preferably C 1- C4 alkyl;

[0011] R2 is selected from phenyl, substituted phenyl, naphthyl or substituted naphthyl, preferably phenyl;

[0012] R3 is selected from hydrogen or C 1- C3 alkyl.

[0013] Furthermore, R3 is selected from hydrogen or propyl, and the structure is shown in formula I or formula II:

[0014]

[0015] Wherein, R1 is selected from C 1- C6 alkyl, substituted C 1- C6 alkyl or C 3- C6 cycloalkyl, preferably C 1- C4 alkyl;

[0016] R2 is selected from phenyl, substituted phenyl, naphthyl or substituted naphthyl, preferably phenyl.

[0017] The second object of the present invention is to provide a preparation method of the above rotigotine intermediate. The preparation method of the compound shown in formula I includes the following steps: 5-methoxy-2-tetralone reacts with chiral 2-amino-2-aryl acetate under the action of a reducing agent to carry out reductive amination reaction to generate the compound shown in formula I:

[0018]

[0019] Wherein, R1 and R2 are as described above.

[0020] Furthermore, 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.

[0021] Further, the molar ratio of the 5-methoxy-2-tetralone to the chiral 2-amino-2-aryl acetate is 1:1 to 5, preferably 1:1 to 2; the reducing agent is selected from one or more of NaBH4, NaBH3CN, and NaBH(OAc)3, preferably NaBH3CN; the molar ratio of the 5-methoxy-2-tetralone to the reducing agent is 1:0.5 to 4, preferably 1:0.5 to 1.5; the solvent used in the reductive amination reaction is selected from one or more of C1-C4 alkyl alcohols, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably N,N-dimethylformamide; the reaction temperature of the reductive amination reaction is -30 to 50 °C, preferably -10 to 30 °C.

[0022] Further, the method for preparing the compound represented by the formula II includes the following steps: The compound represented by the formula I reacts with propionaldehyde under the action of a reducing agent to carry out a reductive amination reaction to generate the compound represented by the formula II

[0023]

[0024] Wherein, R1 and R2 are as described above.

[0025] Further, the molar ratio of the compound represented by the formula I to propionaldehyde is 1:1 to 5, preferably 1:1 to 2; the reducing agent is selected from one or more of NaBH4, NaBH3CN, and NaBH(OAc)3, preferably NaBH(OAc)3; the molar ratio of the compound represented by the formula I to the reducing agent is 1:0.5 to 4, preferably 1:0.5 to 2; the solvent used in the reductive amination reaction is selected from one or more of C1-C4 alkyl alcohols, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably acetonitrile; the reaction temperature of the reductive amination reaction is -30 to 50 °C, preferably 0 °C to 40 °C.

[0026] The third object of the present invention is to provide the application of the above-mentioned rotigotine intermediate in the preparation of rotigotine.

[0027] Further, the method for preparing rotigotine includes the following steps:

[0028] Step a, the compound represented by the formula II is subjected to a catalytic hydrogenation reaction under the action of a hydrogenation reagent to remove the phenylacetate to obtain intermediate III;

[0029] Step b, intermediate III and raw material V carry out a nucleophilic substitution reaction under alkaline conditions to obtain intermediate IV;

[0030] Step c: The intermediate Ⅳ undergoes a demethylation reaction to obtain rotigotine:

[0031]

[0032] Wherein, R1 and R2 are as described above.

[0033] Furthermore, 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 one or two or more of C1-C4 alkyl alcohols, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetic acid, acetonitrile, N , N -dimethylformamide; the reaction temperature of the catalytic hydrogenation reaction is 0-50 °C;

[0034] The basic reagent used in the nucleophilic substitution reaction is selected from one or two or more of sodium carbonate, potassium carbonate, sodium sulfite, N , N -diisopropylethylamine, preferably sodium carbonate; the solvent used in the nucleophilic substitution reaction is selected from one or two or more of C1-C4 alkyl alcohols, water, dimethyl sulfoxide, N -methylpyrrolidone, toluene, xylene, acetonitrile, N , N -dimethylformamide, N , N -dimethylacetamide; the reaction temperature of the nucleophilic substitution reaction is 50-140 °C;

[0035] The reagent for the demethylation reaction is selected from aqueous hydrobromic acid, 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, acetonitrile; the reaction temperature of the demethylation reaction is 0-100 °C.

[0036] Furthermore, the preparation method of rotigotine further includes step a': The compound of the structure shown in formula Ⅰ undergoes a reductive amination reaction with propionaldehyde under the action of a reducing agent to obtain the compound of the structure shown in formula Ⅱ:

[0037]

[0038] Wherein, R1 and R2 are as described above.

[0039] Furthermore, the preparation method of rotigotine further includes step a": 5-Methoxy-2-tetralone undergoes a reductive amination reaction with chiral 2-amino-2-arylacetate under the action of a reducing agent to generate the compound of the structure shown in formula Ⅰ:

[0040]

[0041] Among them, R1 and R2 are as described above.

[0042] Furthermore, the preparation method of rotigotine includes the following steps:

[0043] 5-Methoxy-2-tetralone reacts with chiral 2-amino-2-aryl acetate under the action of a reducing agent to carry out reductive amination reaction, and a compound with the structure shown in Formula I with high optical purity can be obtained; the reducing agent for the reductive amination reaction is selected from NaBH3CN, and the temperature of the reductive amination reaction is -10 - 30 °C;

[0044] The compound with the structure shown in Formula I reacts with propionaldehyde under the action of the reducing agent NaBH(OAc)3 to carry out reductive amination reaction to obtain a compound with the structure shown in Formula II;

[0045] The compound with the structure shown in Formula II undergoes catalytic hydrogenation reaction under the catalysis of palladium / carbon to remove aryl acetate to obtain Intermediate III; the solvent for the catalytic hydrogenation reaction is selected from acetic acid;

[0046] Intermediate III and Intermediate V carry out nucleophilic substitution reaction under alkaline conditions to obtain Intermediate IV; the alkaline reagent used for the nucleophilic substitution reaction is selected from sodium carbonate, and the solvent used is selected from water;

[0047] Intermediate IV undergoes demethylation reaction to obtain rotigotine; the reagent for the demethylation reaction is selected from aluminum trichloride, and the solvent used is selected from toluene:

[0048] .

[0049] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0050] The present invention innovatively uses cheap and easily available chiral 2-amino-2-aryl acetate as the starting material, and prepares a rotigotine intermediate with high optical purity through chiral induction. The rotigotine is prepared from the intermediate. The reaction conditions are mild, the operation is simple, the yield is high, the three wastes are less, and it is more suitable for large-scale industrial production.

[0051] The preparation method of the starting material chiral 2-amino-2-aryl acetate innovatively used in the present invention is simple, and it can be obtained by carrying out an esterification reaction between chiral phenylglycine and the corresponding alkyl alcohol. Specific Embodiments

[0052] The principles and features of the present invention will be described below in conjunction with embodiments. The embodiments given are only used to explain the present invention and are not intended to limit the scope of the present invention. Those skilled in the art should understand that there are other synthetic routes to form the compounds of the present invention, and the following are non-limiting examples.

[0053] Example 1

[0054] Formula I-1: Preparation of methyl 2-(((5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-phenylacetate hydrochloride: S )-2-((( S )-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-phenylacetate hydrochloride:

[0055]

[0056] Into a 250 mL two-necked flask, 5-methoxy-2-tetralone (17.6 g, 100 mmol, 1.0 eq), S )-methyl 2-amino-2-phenylacetate hydrochloride (21.1 g, 105 mmol, 1.05 eq) were added, N , N N,N-dimethylformamide (54.0 g, 3 g / g). While stirring, the internal temperature was brought to 5 °C, and then sodium cyanoborohydride (9.4 g, 150 mmol, 1.5 eq) was added in portions. The reaction was stirred at 5 °C for 6 hours. After monitoring the reaction by HPLC and ensuring its completion (ee value of the reaction solution was 99.2%), the reaction was quenched with water. The reaction mixture was concentrated under reduced pressure at 55 °C to remove part of N,N-dimethylformamide, and then water and toluene were added for extraction. After liquid separation, the organic phase was washed with water once, and the organic phase was collected. While stirring, ethyl acetate-HCl solution was added dropwise to form a salt until the pH value reached 1, and a solid precipitated. The solid was filtered by suction, and the filter cake was rinsed with toluene and then dried to obtain 27.7 g of an off-white solid with a yield of 85.1% and an ee value of 100%, which was compound I-1.

[0057] MS m / z (ESI): 326.19[M+1]. 1 1H NMR (400 MHz, DMSO- d 6) δ 10.03 (d, J J = 25.8Hz, 1H), 7.71 (ddd, J J = 9.5, 6.8, 2.2 Hz, 2H), 7.48 (qt, J J = 5.3, 3.0 Hz, 3H),7.10 (td, J 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).

[0058] Example 2

[0059] Formula Ⅰ-2: Preparation of ethyl 2-(((( S ))-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-phenylacetate hydrochloride: S To a 500 mL two-necked flask, add 5-methoxy-2-tetralone (50.4 g, 286 mmol, 1.0 eq),

[0060]

[0061] ((( S ))-ethyl 2-amino-2-phenylacetate hydrochloride (64.8 g, 300 mmol, 1.05 eq), N , N N,N-dimethylformamide (150.0 g, 3 g / g). Stir until the internal temperature reaches 5°C, and then add sodium cyanoborohydride (26.9 g, 429 mmol, 1.5 eq) portionwise. Stir and react at 5°C for 6 hours. After monitoring the reaction to completion by HPLC (ee value of the reaction solution is 100%), quench the reaction with water. Concentrate under reduced pressure at 55°C to remove part of the N,N-dimethylformamide, add water and toluene for extraction, separate the layers, wash the organic phase with water once, collect the organic phase, and add ethyl acetate-HCl solution dropwise with stirring to form a salt until the pH value reaches 1. A solid precipitates, filter by suction, wash the filter cake with toluene, and dry to obtain 92.7 g of a white solid, with a yield of 86.2% and an ee value of 100%, which is compound Ⅰ-2.

[0062] MS m / z (ESI): 340.21[M + 1]. 1 H 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).

[0063] Example 3

[0064] Formula I - 3: Preparation of isopropyl 2 - (((5 - methoxy - 1,2,3,4 - tetrahydronaphthalen - 2 - yl)amino)-2 - phenylacetate hydrochloride): S ) - 2 - (( S ) - 5 - methoxy - 1,2,3,4 - tetrahydronaphthalen - 2 - yl)amino)-2 - phenylacetate hydrochloride):

[0065]

[0066] To a 100 mL two - necked flask, add 5 - methoxy - 2 - tetralone (5.0 g, 28.4 mmol, 1.0 eq), S ) - 2 - amino - 2 - phenylisopropyl acetate hydrochloride (6.8 g, 29.8 mmol, 1.05 eq), N , N N,N - dimethylformamide (15.0 g, 3 g / g). Stir until the internal temperature reaches 5°C, and then gradually add sodium cyanoborohydride (2.7 g, 42.6 mmol, 1.5 eq) in portions. Stir the reaction at 5°C for 6 hours. After monitoring the reaction to completion by HPLC (ee value of the reaction solution is 98.6%), quench the reaction with water. Concentrate under reduced pressure at 55°C to remove part of N,N - dimethylformamide, add water and toluene for extraction, separate the layers, wash the organic phase with water once, collect the organic phase, and dropwise add ethyl acetate - HCl solution to form a salt until the pH value reaches 1. A solid precipitates, filter by suction, wash the filter cake with toluene, and dry to obtain 9.5 g of a white solid, with a yield of 85.5% and an ee value of 99.2%, which is compound I - 3.

[0067] MS m / z (ESI): 354.25[M + 1]. 1 1H NMR (400 MHz, DMSO - d6) δ 9.84 (s, 1H), 7.66 (ddd, J J = 10.1, 6.5, 2.1 Hz, 2H), 7.49 (td, J J = 5.1, 1.8 Hz, 3H), 7.11 (td, J J = 7.9, 2.6 Hz, 1H), 6.77 (dt, J J = 8.3, 1.4 Hz, 1H), 6.67 (dd, J J = 20.7, 7.7 Hz, 1H), 5.56 - 5.41 (m, 1H), 3.73 (d, J J = 5.2 Hz, 2H), 3.27 - 2.78 (m, 4H), 2.38 (q, J J = 8.7, 7.9 Hz, 2H), 1.78 (dd, J J = 10.8, 5.6 Hz, 1H), 1.24 (t, J J = 6.0 Hz, 3H), 1.04 (dd, J J = 6.2, 3.1 Hz, 3H).

[0068] Example 4

[0069] Formula Ⅰ - 4: Preparation of n - propyl 2 - (((5 - methoxy - 1,2,3,4 - tetrahydronaphthalen - 2 - yl)amino)-2 - phenylacetate hydrochloride: S )-2 - (( S )-5 - methoxy - 1,2,3,4 - tetrahydronaphthalen - 2 - yl)amino)-2 - phenylacetate hydrochloride:

[0070]

[0071] Into a 100 mL two - necked flask, add 5 - methoxy - 2 - tetralone (10.0 g, 56.8 mmol, 1.0 eq), S )-2 - amino - 2 - phenylacetate n - propyl hydrochloride (13.6 g, 59.6 mmol, 1.05 eq), N , N-Dimethylformamide (30.0 g, 3 g / g), while stirring until the internal temperature reaches 5 °C, sodium cyanoborohydride (5.4 g, 85.2 mmol, 1.5 eq) was added portionwise. The reaction was stirred at 5 °C for 6 hours. After the reaction was monitored by HPLC to be complete (the ee value of the reaction solution was 100%), the reaction was quenched with water. The reaction mixture was concentrated under reduced pressure at 55 °C to remove part of N,N-dimethylformamide, then water and toluene were added for extraction. After liquid separation, the organic phase was washed with water once, and the organic phase was collected. While stirring, an ethyl acetate-HCl solution was added dropwise to form a salt until the pH value reached 1, and a solid precipitated. The solid was filtered by suction, and 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%, which was compound Ⅰ-4.

[0072] 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).

[0073] Example 5

[0074] Formula Ⅰ-5: Preparation of compound ( S )-2-((( S )-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-2-phenylacetic acid tert-butyl ester hydrochloride:

[0075]

[0076] Into a 250 mL two-necked flask, 5-methoxy-2-tetralone (25.2 g, 143 mmol, 1.0 eq) was added,( S )-tert-butyl 2-amino-2-phenylacetate hydrochloride (36.6 g, 150.1 mmol, 1.05 eq), N , N N,N-dimethylformamide (75.6 g, 3 g / g). The mixture was stirred until the internal temperature reached 5 °C, and then sodium cyanoborohydride (13.5 g, 214.5 mmol, 1.5 eq) was added portionwise. The reaction was stirred at 5 °C for 6 hours. After the reaction was monitored by HPLC to be complete (the ee value of the reaction solution was 98.4 %), the reaction was quenched with water. Part of N,N-dimethylformamide was removed by concentration under reduced pressure at 55 °C. Water and toluene were added for extraction. After liquid separation, the organic phase was washed with water once. The organic phase was collected and an ethyl acetate-HCl solution was added dropwise with stirring to form a salt until the pH value reached 1. A solid precipitated, which was filtered by suction. The filter cake was rinsed 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 %, namely compound Ⅰ-5.

[0077] MS m / z (ESI): 404.91[M+1]. 1 1H 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 J = 7.9, 2.4 Hz, 1H), 6.75(dd, J J = 8.2, 2.5 Hz, 1H), 6.66 (dd, J J = 20.4, 7.7 Hz, 1H), 5.34 (d, J J = 17.3 Hz,1H), 3.73 (d, J J = 5.1 Hz, 3H), 3.25-2.77 (m, 4H), 2.44-2.30 (m, 2H), 1.80 (dq, J J = 11.9, 6.6, 6.2 Hz, 1H), 1.37 (s, 10H).

[0078] Example 6

[0079] Formula Ⅱ-1: Preparation of compound( S )-2-((( S )-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)-2-phenylacetic acid methyl ester:

[0080]

[0081] To a 500 mL two-necked flask, add 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), stir until dissolved and clear, cool to 5 °C, add sodium triacetoxyborohydride (32.2 g, 152 mmol, 2.0 eq), react at 40 °C for 5 hours, monitor the reaction by HPLC until completion, cool down, quench the reaction with water, concentrate and rotary evaporate to dryness, add toluene and water for extraction and liquid separation, extract the organic phase once with saturated aqueous sodium bicarbonate solution, collect the organic phase, concentrate and rotary evaporate to dryness to obtain 27.9 g of a yellowish-brown oily substance, which is compound II-1, directly used for the next reaction, with a yield of 100%, MS m / z (ESI): 368.41 [M+1].

[0082] Example 7

[0083] Formula II-2: Preparation of compound ( S )-2-((( S )-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(n-propyl)amino)-2-phenylacetic acid ethyl ester:

[0084]

[0085] To a 1000 mL two-necked flask, add compound I-2 (92.1 g, 245 mmol, 1.0 eq), acetonitrile (368 g, 4 g / g), propionaldehyde (25.6 g, 441 mmol, 1.8 eq), stir until dissolved and clear, cool to 5 °C, add sodium triacetoxyborohydride (103.8 g, 490 mmol, 2.0 eq), react at 40 °C for 5 hours, monitor the reaction by HPLC until completion, cool down, quench the reaction with water, concentrate and rotary evaporate to dryness, add toluene and water for extraction and liquid separation, extract the organic phase once with saturated aqueous sodium bicarbonate solution, collect the organic phase, concentrate and rotary evaporate to dryness to obtain 93.4 g of a yellowish-brown oily substance, which is compound II-2, directly used for the next reaction, with a yield of 100%, MS m / z (ESI): 382.32 [M+1].

[0086] Example 8

[0087] Formula II-3: Preparation of compound ( S )-2-((( S )-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(n-propyl)amino)-2-phenylacetic acid isopropyl ester:

[0088]

[0089] Into a 100 mL two-necked flask, add 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), stir until clear, cool to 5 °C, add sodium triacetoxyborohydride (10.0 g, 47.2 mmol, 2.0 eq), react at 40 °C for 5 hours, monitor the reaction by HPLC until completion, cool down, quench the reaction with water, concentrate and rotary evaporate to dryness, add toluene and water for extraction and liquid separation, extract the organic phase once with saturated aqueous sodium bicarbonate solution, collect the organic phase, concentrate and rotary evaporate to dryness to obtain 9.3 g of a yellowish-brown oily substance, which is compound II-3, directly used for the next reaction, with a yield of 100%, MS m / z (ESI): 396.22 [M+1].

[0090] Example 9

[0091] Formula II-4: Preparation of compound ( S )-2-((( S )-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)-2-phenylacetic acid n-propyl ester:

[0092]

[0093] Into a 100 mL two-necked flask, add compound I-4 (18.0 g, 46.2 mmol, 1.0 eq), acetonitrile (72 g, 4 g / g), propionaldehyde (4.8 g, 83.1 mmol, 1.8 eq), stir until clear, cool to 5 °C, add sodium triacetoxyborohydride (19.6 g, 92.3 mmol, 2.0 eq), react at 40 °C for 5 hours, monitor the reaction by HPLC until completion, cool down, quench the reaction with water, concentrate and rotary evaporate to dryness, add toluene and water for extraction and liquid separation, extract the organic phase once with saturated aqueous sodium bicarbonate solution, collect the organic phase, concentrate and rotary evaporate to dryness to obtain 18.3 g of a yellowish-brown oily substance, which is compound II-4, directly used for the next reaction, with a yield of 100%, MS m / z (ESI): 396.22 [M+1].

[0094] Example 10

[0095] Formula II-5: Preparation of compound ( S )-2-((( S )-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)-2-phenylacetic acid tert-butyl ester:

[0096]

[0097] Into a 100 mL two-necked flask, add compound I-5 (50.2 g, 124.2 mmol, 1.0 eq), acetonitrile (201 g, 4 g / g), propionaldehyde (13.0 g, 224 mmol, 1.8 eq), stir until dissolved and clear, cool down to 5 °C, add sodium triacetoxyborohydride (52.7 g, 248.6 mmol, 2.0 eq), react at 40 °C for 5 hours, monitor the reaction by HPLC until completion, cool down, quench the reaction with water, concentrate and rotary evaporate to dryness, add toluene and water for extraction and liquid separation, extract the organic phase once with saturated sodium bicarbonate aqueous solution, collect the organic phase, concentrate and rotary evaporate to dryness to obtain 50.9 g of a yellowish-brown oily substance, which is compound II-5, directly used for the next reaction, with a yield of 100%, MS m / z (ESI): 410.26[M+1].

[0098] Example 11

[0099] Formula III: Compound ( S )-5-methoxy- N -propyl-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride preparation:

[0100]

[0101] Into a 500 mL single-necked round-bottom flask, add compound II-2 (50 g, 131 mmol, 1.0 eq), dissolve in acetic acid (200 g, 4 g / g), add palladium on carbon (2.0 g, 4 %w / w), displace with hydrogen three times, react at 45 °C for 10 hours, monitor the reaction by HPLC until completion, filter off the palladium on carbon, wash the filter cake with acetic acid, collect the filtrate, concentrate and rotary evaporate to dryness, dissolve in ethanol, add concentrated hydrochloric acid dropwise thereto with stirring, precipitate a solid, adjust the pH value to 1, filter, wash 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 the two steps is 95.5%.

[0102] 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).

[0103] Example 12

[0104] Formula IV: Compound ( S ) - 5 - methoxy - N - propyl - N -(2 - (thiophen - 2 - yl)ethyl)-1,2,3,4 - tetrahydronaphthalen - 2 - amine Preparation:

[0105]

[0106] In a 250 mL single - necked 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 and refill with nitrogen three times. React at 100 °C for 10 hours. Monitor the reaction by HPLC until completion. Add toluene and water for extraction and liquid separation. Collect the organic phase, wash the organic phase with water once, rotary - evaporate the organic phase to dryness, dissolve it in methyl tert - butyl ether, and dropwise add ethyl acetate - HCl to form a salt while stirring. A solid precipitates, filter by suction, wash the filter cake with methyl tert - butyl ether, and dry to obtain 42.7 g of a white solid, which is the compound of formula IV, with a yield of 93.4%.

[0107] 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)

[0108] Example 13

[0109] Formula Ⅴ: Preparation of Rotigotine:

[0110]

[0111] In a 250 mL single-necked round-bottom flask, add the compound of Formula Ⅳ (10.0 g, 27.3 mmol, 1.0 eq), anhydrous aluminum trichloride (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). React at 70 °C for 6 h. Monitor the reaction by HPLC until completion. Evaporate the solvent under reduced pressure, add water dropwise to quench the reaction, adjust the pH value to 9 with saturated sodium carbonate aqueous solution, extract with dichloromethane, wash with water, combine the organic phases, spin dry, add ethanol and water, cool to about -10 °C for recrystallization, precipitate a solid, filter by suction, and wash the filter cake with cold ethanol to obtain 7.8 g of an off-white solid, with a yield of 90.3%.

[0112] 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).

[0113] The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within 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 salts: Among them, R1 is selected from C 1- alkyl groups having 6 carbon atoms; R2 is selected from phenyl; R3 is selected from hydrogen or C 1- C3 alkyl.

2. The rotigotine intermediate according to claim 1, wherein R3 is selected from hydrogen or propyl, and the structure is shown in Formula I or Formula II: Among them, R1 is selected from C 1- alkyl groups having 1 to 6 carbon atoms; R2 is selected from phenyl.

3. A preparation method of the rotigotine intermediate as described in claim 2, characterized in that, The preparation method of the compound with the structure shown in Formula I includes the following steps: 5-methoxy-2-tetralone undergoes reductive amination reaction with chiral 2-amino-2-aryl acetate under the action of a reducing agent to generate the compound with the structure shown in Formula I.

4. The preparation method of the rotigotine intermediate according to claim 3, characterized in that, The chiral 2-amino-2-aryl acetate is selected from methyl (S)-2-amino-2-phenylacetate, ethyl (S)-2-amino-2-phenylacetate, n-propyl (S)-2-amino-2-phenylacetate, isopropyl (S)-2-amino-2-phenylacetate or tert-butyl (S)-2-amino-2-phenylacetate.

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

6. The preparation method of the rotigotine intermediate according to claim 3, wherein, The preparation method of the compound with the structure shown in Formula II includes the following steps: The compound with the structure shown in Formula I undergoes reductive amination reaction with propionaldehyde under the action of a reducing agent to generate the compound with the structure shown in Formula II.

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

8. Use of a rotigotine intermediate as described in claim 1 in the preparation of rotigotine.

9. Use of a rotigotine intermediate as described in claim 2 in the preparation of rotigotine.

10. The application according to claim 9, wherein The preparation method of the rotigotine includes the following steps: Step a, the compound with the structure shown in Formula II undergoes catalytic hydrogenation reaction under the action of a hydrogenation reagent to remove phenylacetate and 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 undergoes demethylation reaction to obtain rotigotine: 。 11. The application according to claim 10, wherein The hydrogenation reagent is selected from palladium / carbon or palladium hydroxide / carbon; the solvent used in the catalytic hydrogenation reaction is selected from one or more of C1-C4 alkyl alcohols, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetic acid, acetonitrile, N , N N,N-dimethylformamide; the reaction temperature of the catalytic hydrogenation reaction is 0 to 50 °C; The basic reagent used in the nucleophilic substitution reaction is selected from one or more of sodium carbonate, potassium carbonate, N , N -diisopropylethylamine; the solvent used in the nucleophilic substitution reaction is selected from one or more of C1-C4 alkyl alcohols, water, dimethyl sulfoxide, N -methylpyrrolidone, toluene, xylene, acetonitrile, N , N -dimethylformamide, N , N -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, boron tribromide or aluminum trichloride; the solvent used for the demethylation reaction is selected from one or more of dichloromethane, toluene, xylene, and acetonitrile; the reaction temperature of the demethylation reaction is 0 to 100 °C.

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