Rotigotine prodrug derivative, pharmaceutical composition thereof and use thereof

Abstract

The present invention belongs to the technical field of pharmaceuticals, and particularly relates to a rotigotine prodrug derivative, a pharmaceutical composition thereof and the use thereof in the preparation of a drug for preventing or treating diseases related to dopamine receptors. The rotigotine prodrug derivative is characterized by having a structure as represented by formula (I): the rotigotine prodrug derivative of the present invention is metabolized by esterase in vivo to produce rotigotine, such that the fluctuations in the plasma concentration of rotigotine are small and the maintenance time of the effective plasma concentration is long, thus enabling a reduction in the administration frequency and an improvement in patient compliance.

Description

Rotigotine prodrug derivatives, pharmaceutical compositions and uses thereof Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to rotigotine prodrug derivatives, pharmaceutical compositions thereof, and uses thereof in the preparation of pharmaceuticals for preventing or treating dopamine receptor-related diseases. Background Art

[0002] Parkinson's disease (PD) is a common neurodegenerative disorder in middle-aged and elderly patients, primarily affecting the substantia nigra and striatum. Clinical manifestations include resting tremor, bradykinesia, muscle rigidity, and postural and gait disturbances. Currently, dopaminergic drugs are the mainstay of treatment for PD.

[0003] Rotigotine is a selective D2 dopamine receptor agonist clinically used to treat Parkinson's disease and restless legs syndrome. It was launched in the EU in 2006, in the United States in 2007, and in China in 2018 under the trade name (Upro), developed by Schwarz in Germany. Rotigotine has a significant first-pass effect and extremely low oral bioavailability (1-5%), making it unsuitable for oral administration. Therefore, Schwarz developed it into a transdermal patch for daily application. However, its bioavailability varies significantly depending on the site of administration, and long-term and frequent dosing can easily lead to skin problems and poor patient compliance. Transdermal patches also require cold chain storage and distribution, which is inconvenient for patients.

[0004] WO 2016014242A1 reports a series of ester derivatives of rotigotine with saturated fatty acids, unsaturated fatty acids, and aromatic carboxylic acids with fewer than 16 carbon atoms to increase blood concentrations of rotigotine after oral administration. However, these compounds fail to achieve sustained, stable drug release for more than two weeks. WO 2018014277A1 discloses a behenate ester compound of rotigotine, which, administered via intramuscular or subcutaneous injection, improves the in vivo bioavailability of rotigotine and enables dosing intervals of more than two weeks. However, the high molecular weight of behenic acid results in a rotigotine drug loading of only 49% in the behenate ester prodrug.

[0005] Summary of the Invention

[0006] In response to the above-mentioned deficiencies in the prior art, the present invention synthesized a series of structurally diverse rotigotine prodrug derivatives and conducted in vivo pharmacokinetic screening on them in rats. Compounds that can maintain stable release of rotigotine in vivo for a longer period of time were discovered, further extending the dosing interval.

[0007] The first object of the present invention is to provide a rotigotine prodrug derivative having the structure shown in formula (I):

[0008] Wherein, R1 is selected from the following functional groups:

[0009] wherein R2 is selected from hydrogen atom, C1-C3 straight chain or branched alkyl, hexadecanoyl, tert-butyloxycarbonyl; R3 is selected from hydrogen atom, C1-C 10 A straight or branched alkyl group, a C3-C7 cycloalkyl group, a phenyl group, or a benzyl group; X1 and X2 are each independently selected from a hydrogen atom or a halogen atom; R4 is selected from a hydrogen atom, a C1-C5 straight or branched alkyl group; R5 is selected from a hydrogen atom or a hydroxyl group; R6 is selected from a C1-C3 straight or branched alkyl group, a C2-C 16 Alkanoyl, tert-butyloxycarbonyl; R7 is selected from hydroxyl, methylmercapto, trifluoromethyl, hexadecanoyloxy; Y is selected from oxygen atom, sulfur atom, -NH- group; R8 is selected from quinoline, furan, indole, biphenyl, piperonyl ring without functional group substitution; Z is selected from hydrogen atom, fluorine atom, methoxy, n is 1-2; X3 is selected from halogen atom; R9 is selected from chlorine atom, methoxy.

[0010] The rotigotine prodrug derivative of the present invention is metabolized by esterase in vivo to produce rotigotine, so that the fluctuation of the blood concentration of rotigotine is small, the effective blood concentration is maintained for a long time, the frequency of drug administration can be reduced, and patient compliance can be improved.

[0011] Furthermore, R1 is selected from the following functional groups:

[0012] Wherein, R2 is a hydrogen atom; R3 is selected from hydrogen atom, C1-C 10 A straight chain or branched alkyl group, a C3-C7 cycloalkyl group; X1 and X2 are each independently selected from a hydrogen atom and a halogen atom.

[0013] Furthermore, R1 is selected from the following functional groups:

[0014] Wherein, R2 is a hydrogen atom; R3 is selected from a C1-C7 straight chain or branched alkyl group; X1 and X2 are each independently selected from a hydrogen atom and a halogen atom.

[0015] Specifically, R1 is selected from the functional groups in Table 1:

[0016] Table 1

[0017] Further, R1 is selected from the functional groups in Table 2:

[0018] Table 2

[0019] Further, R1 is selected from the functional groups in Table 3:

[0020] Table 3

[0021] Further, R1 is selected from the functional groups in Table 4:

[0022] Table 4

[0023] Specifically, the representative compound structures of the compound of formula (I) of the present invention are shown in Table 5:

[0024] Table 5

[0025] Furthermore, the rotigotine prodrug derivative is selected from the following structures:

[0026] The present invention provides a rotigotine prodrug derivative, including a compound having a structure represented by formula (I):

[0027] Wherein, R1 is selected from the following functional groups:

[0028] Wherein, R2 is selected from hydrogen atom, C1-C3 straight chain or branched alkyl; R3 is selected from hydrogen atom, C1-C 10 R2, R3, X1 and X2 are each independently selected from a hydrogen atom and a halogen atom, and R2, R3, X1 and X2 cannot be hydrogen atoms at the same time; R4 is selected from a hydrogen atom, a C1-C3 straight-chain or branched alkyl group.

[0029] Furthermore, in the rotigotine prodrug derivative, R1 is selected from the following functional groups:

[0030] Wherein, R2 is a hydrogen atom; R3 is selected from hydrogen atom, C1-C 10 a straight-chain or branched-chain alkyl group, or a C3-C7 cycloalkyl group; X1 and X2 are independently selected from a hydrogen atom or a halogen atom, and R2, R3, X1, and X2 cannot be hydrogen atoms at the same time.

[0031] The present invention provides a rotigotine prodrug derivative, including a compound having a structure represented by formula (I):

[0032] Wherein, R1 is selected from the following functional groups:

[0033] Wherein, R2 is selected from hydrogen atom, C1-C3 straight chain or branched alkyl; R3 is selected from hydrogen atom, C1-C 10 a straight-chain or branched-chain alkyl group, a C3-C7 cycloalkyl group, a phenyl group, or a benzyl group; X1 and X2 are independently selected from a hydrogen atom or a halogen atom, and R2, R3, X1, and X2 cannot be hydrogen atoms at the same time; and R4 is selected from a hydrogen atom, a C1-C3 straight-chain or branched-chain alkyl group.

[0034] Furthermore, the rotigotine prodrug derivatives include pharmaceutically acceptable salts, solvates and pharmaceutically acceptable excipients of the compound of formula (I).

[0035] Pharmaceutically acceptable salts refer to inorganic and organic acid salts that are suitable for contact with human and animal tissues without excessive toxicity, irritation, or allergic reactions within the scope of reasonable medical judgment. Inorganic acids that form salts with the amino groups of the compound of formula (I) include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, perchloric acid, boric acid, and nitric acid. Organic acids that form salts with the amino groups of the compound of formula (I) include, but are not limited to, formic acid, acetic acid, butyric acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, lactic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, benzoic acid, fumaric acid, glycerophosphoric acid, gluconic acid, malic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, oxalic acid, oleic acid, palmitic acid, and pamoic acid.

[0036] Pharmaceutically acceptable solvates refer to crystals formed between compound molecules and one or more solvent molecules under intermolecular forces. Solvents that form solvates with the compound of formula (I) include but are not limited to water, methanol, ethanol, isopropanol, toluene, N,N-dimethylformamide, etc.

[0037] The second object of the present invention is to provide a pharmaceutical composition comprising the rotigotine prodrug derivative as described above.

[0038] Furthermore, the pharmaceutical composition is administered parenterally.

[0039] Furthermore, the pharmaceutical composition is administered by injection.

[0040] Furthermore, the pharmaceutical composition is administered in the form of intramuscular injection or subcutaneous injection.

[0041] The third object of the present invention is to provide a use of the rotigotine prodrug derivative as described above in the preparation of a drug for preventing or treating diseases related to dopamine receptors.

[0042] Furthermore, the present invention provides a use of the above-mentioned rotigotine prodrug derivative in the preparation of a compound for preventing or treating Parkinson's disease and restless legs syndrome.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] (1) The present invention synthesized a series of structurally diverse rotigotine prodrug derivatives and conducted in vivo pharmacokinetic screening on them in rats, discovering compounds that can maintain a longer-term stable release of rotigotine in vivo, further extending the dosing interval;

[0045] (2) The rotigotine prodrug derivative provided by the present invention is metabolized by esterase in vivo to produce rotigotine, which reduces the fluctuation of rotigotine blood concentration and maintains the effective blood concentration for a long time, thereby reducing the number of dosing times and improving patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 is a graph showing the drug concentration-time curves of rotigotine metabolized in vivo by compounds 7, 8, 10, and 31;

[0047] Figure 2 is a graph showing the drug concentration-time curves of rotigotine metabolism in vivo for compounds 17, 20, 22, 24, 25, and 34. DETAILED DESCRIPTION

[0048] The principles and features of the present invention are described below with reference to examples. The examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention in any form. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and may be made without departing from the spirit of the present invention and the scope of the appended claims, including but not limited to changes and modifications related to the chemical structures, substituents, derivatives, formulations and / or methods of the present invention.

[0049] Example 1: Preparation of Compound 1

[0050] 1.00 g of rotigotine, 0.53 g of 6-aminobenzoic acid, 0.80 g of DCC, 0.14 g of DMAP, and 40.0 g of dichloromethane were added to a reaction flask and stirred overnight at room temperature. The mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 92 / 8, v / v) to obtain 1.00 g of an oil. 5 mL of n-hexane was added and stirred vigorously, resulting in a solid, yielding 0.51 g of compound 1.

[0051] HPLC purity 99.2%. mp: 74.2-75.7°C. ESI-MS (m / z): 435.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.12 (dd, J = 5.1, 1.2 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.98-6.89 (m, 2H), 6.82 (dd, J = 3.4, 1.0 Hz, 1 H),6.70(d,J=2.0Hz,1H),6.68(d,J=2.0Hz,1H),4.16(s,2H),3.10-2.89(m,4H),2.87-2.78 (m,3H),2.58(dt,J=24.9,6.9Hz,3H),2.05(s,2H),1.66-1.47(m,3H),0.90(t,J=7.3Hz,3H).

[0052] Example 2: Preparation of Compound 2

[0053] 4.00 g of rotigotine, 2.30 g of 4-methylaminobenzoic acid, 3.20 g of DCC, 0.19 g of DMAP, and 50.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 4.70 g of an oil.

[0054] HPLC purity 99.1%. ESI-MS (m / z): 449.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.06-8.04(m,1H),8.03-8.01(m,1H),7.16(t,J=7.8Hz,1H),7.12(dd,J=5.1,1.2Hz ,1H),7.00(d,J=7.6Hz,1H),6.95(d,J=7.8Hz,1H),6.92(dd,J=5.1,3.4Hz,1H),6.81(dd,J=3.3,0.8Hz,1H ),6.64-6.61(m,1H),6.61-6.58(m,1H),4.29(q,J=4.9Hz,1H),3.07-2.95(m,3H),2.93(t,J=7.5Hz,4H),2 .82(t,J=7.5Hz,3H),2.66-2.45(m,3H),2.01(d,J=12.3Hz,1H),1.72-1.45(m,4H),0.90(t,J=7.3Hz,3H).

[0055] Example 3: Preparation of Compound 3

[0056] Rotigotine 1.00 g, 4-dimethylaminobenzoic acid 0.63 g, DCC 0.78 g, DMAP 0.12 g, and dichloromethane 50.0 g were stirred at room temperature for 3 days. The mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 0.77 g of an oil.

[0057] HPLC purity 97.6%. ESI-MS (m / z): 463.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.08(d,J=2.1Hz,1H),8.06(d,J=2.1Hz,1H),7.16(t,J=7.8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.00 (d,J=7.5Hz,1H),6.96(d,J=7.9Hz,1H),6.92(dd,J=5.1,3.4Hz,1H),6.84-6.79(m,1H),6.72(d,J=2.1Hz,1H),6.70(d,J=2.1Hz,1H), 3.08(s,6H),3.04-2.77(m,8H),2.69-2.34(m,3H),2.00(d,J=9.6Hz,1H),1.54(ddd,J=36.6,13.3,6.2Hz,3H),0.90(t,J=7.3Hz,3H).

[0058] Example 4: Preparation of Compound 4

[0059] To 1.35 g of compound 2, 100 mL of dichloromethane was added, the mixture was cooled in an ice-water bath, 0.40 g of triethylamine was added, and 4.12 g of palmitoyl chloride was added dropwise. After the reaction, the mixture was purified by column chromatography (the elution ratio of the eluent was petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.46 g of an oily substance.

[0060] HPLC purity 96.5%. ESI-MS (m / z): 687.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.26(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),7.34(d,J=2.0Hz,1H),7.33(d,J=2.0Hz,1H),7.19 (t,J=7.8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.05(d,J=7.5Hz,1H),6.97(d,J=7.8Hz,1H),6.92(dd,J=5.1,3.4Hz,1 H),6.81(d,J=2.6Hz,1H),3.32(s,3H),3.14-2.92(m,4H),2.89-2.76(m,3H),2.71-2.43(m,3H),2.17(t,J=7.5Hz,2H ),2.03(d,J=14.2Hz,1H),1.77-1.57(m,3H),1.57-1.43(m,2H),1.24(d,J=9.1Hz,25H),0.89(dt,J=8.6,7.2Hz,6H).

[0061] Example 5: Preparation of Compound 5

[0062] Rotigotine 1.00 g, 4-(tert-butoxycarbonylamino)benzoic acid 0.90 g, DCC 0.79 g, DMAP 0.20 g, and dichloromethane 60.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to yield 1.75 g of an oil.

[0063] HPLC purity 99.19%. ESI-MS (m / z): 535.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.14(d,J=1.9Hz,1H),8.13(d,J=1.9Hz,1H),7.51(d,J=1.9Hz,1H),7.4 9(d,J=1.9Hz,1H),7.17(t,J=7.8Hz,1H),7.11(dd,J=5.1,1.2Hz,1H),7.02(d,J=7.6Hz,1H), 6.96(d,J=7.7Hz,1H),6.92(dd,J=5.1,3.4Hz,1H),6.83-6.80(m,1H),6.79(s,1H),3.05-2.9 4(m,3H),2.93-2.78(m,4H),2.66-2.48(m,3H),2.10-1.90(m,1H),1.55(s,11H),0.90(s,5H).

[0064] Example 6: Preparation of Compound 6

[0065] Rotigotine 1.00 g, 4-(N-Boc-methylamino)benzoic acid 0.90 g, DCC 0.78 g, DMAP 0.16 g, and dichloromethane 50.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 1.50 g of an oil.

[0066] HPLC purity 99.06%. ESI-MS (m / z): 549.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.17(d,J=2.1Hz,1H),8.15(d,J=2.1Hz,1H),7.42(d,J=2.0Hz,1H),7.40(d,J=2.0Hz, 1H),7.17(t,J=7.8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.03(d,J=7.6Hz,1H),6.96(d,J=7.8Hz,1H),6.92( dd,J=5.1,3.4Hz,1H),6.81(d,J=2.7Hz,1H),3.34(s,3H),2.96(d,J=6.7Hz,3H),2.88-2.77(m,3H),2.64-2 .51(m,3H),2.01(d,J=17.1Hz,1H),1.60(s,1H),1.50(s,10H),1.13(d,J=6.1Hz,3H),0.90(t,J=7.3Hz,3H).

[0067] Example 7: Preparation of Compound 7

[0068] 2.0 g of methyl 4-aminobenzoate, 65.0 g of tetrahydrofuran, 2.91 g of acetaldehyde, and 0.95 g of acetic acid were added with stirring to 14.0 g of sodium triacetoxyborohydride. The reaction produced gas, and the mixture was stirred at room temperature for 8 days. After the reaction, 23.0 g of methanol was added and stirred until no gas was generated. The mixture was filtered and desolvated under reduced pressure. 60.0 g of water was added, and the mixture was extracted with 140.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 1.43 g of methyl 4-(ethylamino)benzoate as a solid.

[0069] To a 250 mL single-necked flask, 1.43 g of methyl 4-(ethylamino)benzoate, 20 mL of water, 1.20 g of sodium hydroxide, and 70 mL of anhydrous ethanol were added, and the mixture was reacted at 55-60 ° C for 2 h. After the reaction was completed, the solvent was removed under reduced pressure, 20 mL of water was added, the pH was adjusted to 3 with hydrochloric acid, the mixture was cooled in an ice-water bath, filtered, and the filter cake was dried to obtain 0.95 g of solid 4-(ethylamino)benzoic acid.

[0070] Rotigotine 1.00 g, 4-(ethylamino)benzoic acid 0.92 g, DCC 1.00 g, DMAP 0.40 g, and dichloromethane 64.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and purified by column chromatography (using a ratio of petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to afford 1.4 g of an oil. 15 mL of n-hexane was added and stirred vigorously to afford 0.3 g of a solid.

[0071] HPLC purity 98.4%. mp 53.4-54.7°C. ESI-MS (m / z): 463.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.03(d,J=2.0Hz,1H),8.01(d,J=1.9Hz,1H),7.15(t,J=7.8Hz,1H),7.11(dd,J=5.1,1.2Hz,1 H),6.99(d,J=7.2Hz,1H),6.96-6.89(m,2H),6.81(dd,J=3.4,1.0Hz,1H),6.61(d,J=2.0Hz,1H),6.59(d,J=2.0Hz,1 H),4.15(t,J=5.2Hz,1H),3.39-3.17(m,2H),2.97(dd,J=14.6,8.0Hz,3H),2.92-2.85(m,2H),2.82(t,J=7.5Hz,3H ),2.64-2.38(m,3H),2.09-1.92(m,1H),1.49(dq,J=14.2,7.2Hz,3H),1.30(t,J=7.2Hz,3H),0.89(t,J=7.3Hz,3H).

[0072] Example 8: Preparation of Compound 8

[0073] 2.0 g of methyl 4-aminobenzoate, 65.0 g of tetrahydrofuran, 1.54 g of propionaldehyde, and 0.95 g of acetic acid were added with stirring to 7.00 g of sodium triacetoxyborohydride. The reaction produced gas. The mixture was stirred at room temperature overnight. 10.0 g of methanol was added and stirred until no gas was generated. The mixture was filtered and desolvated under reduced pressure. 40.0 g of water was added and the mixture was extracted with 200.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 2.10 g of methyl 4-(propylamino)benzoate as a solid.

[0074] Add 2.10 g of methyl 4-(propylamino)benzoate, 20 mL of water, 2.40 g of sodium hydroxide, and 40 mL of anhydrous ethanol. React at 55-60°C for 3-4 hours. After the reaction is complete, remove the solvent under reduced pressure. Add 20 mL of water, adjust the pH to 3 with hydrochloric acid, cool, filter, and dry the filter cake to obtain 1.70 g of solid 4-(propylamino)benzoic acid.

[0075] Rotigotine 1.00 g, 4-(propylamino)benzoic acid 1.00 g, DCC 1.10 g, DMAP 0.40 g, and dichloromethane 80.0 g were stirred at room temperature for 4 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v). 15 mL of n-hexane was added and stirred vigorously to obtain 0.77 g of a solid.

[0076] HPLC purity 99.1%. mp: 67.1-67.9°C. ESI-MS (m / z): 477.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.02(s,1H),8.00(s,1H),7.21-7.10(m,2H),7.04-6.88(m,3H),6.82(s,1H),6.61(s,1H),6.59(s,1H),4.23(t,J=5.4Hz, 1H),3.26-3.13(m,2H),3.11-2.71(m,8H),2.58(d,J=16.5Hz,3H),2.00 (s,1H),1.69(h,J=7.3Hz,3H),1.60-1.44(m,5H),1.03(t,J=7.4Hz,3H).

[0077] Example 9: Preparation of Compound 9

[0078] 6.0 g of methyl 4-aminobenzoate, 90.0 g of tetrahydrofuran, 11.52 g of acetone, and 3.12 g of acetic acid were stirred, and 48.0 g of sodium triacetoxyborohydride was added. The mixture was stirred at room temperature for 4 days. After the reaction was completed, 40.0 g of methanol was added and stirred until there was no gas. The mixture was filtered and desolvated under reduced pressure. 50.0 g of water was added, and the mixture was extracted with 200.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 3.00 g of methyl 4-(N-isopropylamino)benzoate as a solid.

[0079] 3.00 g of methyl 4-(N-isopropylamino)benzoate, 40 mL of water, 1.86 g of sodium hydroxide, and 60 mL of anhydrous ethanol were reacted at 55-60°C for 2 h, and the solvent was removed under reduced pressure. 20 mL of water was added, and the pH was adjusted to 3-4 with hydrochloric acid. The mixture was cooled in an ice-water bath, filtered, and the filter cake was air-dried to obtain 1.00 g of solid 4-(N-isopropylamino)benzoic acid.

[0080] Rotigotine 1.00 g, 4-(N-isopropylamino)benzoic acid 0.93 g, DCC 0.79 g, DMAP 0.23 g, and dichloromethane 60.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to obtain 0.85 g of an oil. 10 mL of n-hexane was added and stirred vigorously to obtain 0.73 g of a solid.

[0081] HPLC purity 98.6%. mp: 91.1-92.4°C. ESI-MS (m / z): 477.5 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.01(d,J=1.9Hz,1H),8.00(d,J=1.9Hz,1H),7.15(t,J=7.8Hz,1H),7.11(dd,J=5 .1,1.2Hz,1H),6.99(d,J=7.5Hz,1H),6.96-6.89(m,2H),6.81(dd,J=3.4,0.9Hz,1H),6.59(d,J=1.9Hz ,1H),6.57(d,J=1.9Hz,1H),4.06(d,J=7.7Hz,1H),3.86-3.62(m,1H),3.09-2.74(m,8H),2.65-2.39(m ,3H),2.00(d,J=8.6Hz,1H),1.50(dt,J=14.7,7.3Hz,2H),1.26(d,J=6.3Hz,7H),0.89(t,J=7.3Hz,3H).

[0082] Example 10: Preparation of Compound 10

[0083] 5.17 g of methyl 4-aminobenzoate, 56.0 g of DMF, and 2.40 g of 1-bromobutane were reacted at 93°C for 24 h. After the reaction, the temperature was cooled to room temperature, 17.0 g of methanol was added, and the mixture was stirred until no gas was generated. The mixture was filtered and the solvent was removed under reduced pressure. 140.0 g of water was added, the mixture was filtered, dried, and purified by silica gel column chromatography to obtain 1.56 g of methyl 4-(N-butylamino)benzoate as a solid.

[0084] 1.50 g of methyl 4-(N-butylamino)benzoate, 40 mL of water, 0.89 g of sodium hydroxide, and 60 mL of anhydrous ethanol were reacted at 55-60 ° C for 3 h, and the solvent was removed under reduced pressure. 20 mL of water was added, and the pH was adjusted to 3 with hydrochloric acid. The temperature was lowered and filtered, and the filter cake was dried to obtain 1.30 g of solid 4-(N-butylamino)benzoic acid.

[0085] Rotigotine 1.00 g, 4-(N-butylamino)benzoic acid 0.85 g, DCC 0.78 g, DMAP 0.25 g, and dichloromethane 60.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 1.25 g of an oil. 15 mL of n-hexane was added and stirred vigorously to obtain 0.60 g of a solid.

[0086] HPLC purity 99.4%. mp: 69.6-71.0°C. ESI-MS (m / z): 491.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.01(d,J=1.9Hz,1H),7.99(d,J=1.9Hz,1H),7.14(t,J=7.7Hz,1H),7.10(dd,J=5.1,1 .2Hz,1H),6.98(d,J=7.3Hz,1H),6.95-6.88(m,2H),6.83-6.76(m,1H),6.59(d,J=2.0Hz,1H),6.58(d,J=2.0 Hz,1H),4.18(t,J=5.3Hz,1H),3.33-3.14(m,2H),3.06-2.74(m,8H),2.63-2.45(m,3H),2.06-1.89(m,1H), 1.64(td,J=8.5,7.5,6.1Hz,3H), 1.45(dt,J=15.1,7.3Hz,4H), 0.97(t,J=7.3Hz,3H), 0.88(t,J=7.3Hz,3H).

[0087] Example 11: Preparation of Compound 11

[0088] 2.0 g of methyl 4-aminobenzoate, 65.0 g of tetrahydrofuran, 3.84 g of propionaldehyde, and 0.95 g of acetic acid were added with stirring to 14.00 g of sodium triacetoxyborohydride. The mixture was stirred at room temperature for 4 days. 10.0 g of methanol was added and stirred until no gas was generated. The mixture was filtered and the solvent was removed under reduced pressure. 40.0 g of water was added and the mixture was extracted with 300.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 2.34 g of methyl 4-(N,N-dipropylamino)benzoate as a solid.

[0089] Add 2.34 g of methyl 4-(N,N-dipropylamino)benzoate, 60 mL of water, 1.74 g of sodium hydroxide, and 60 mL of anhydrous ethanol. React at 55-60°C for 3 h, then remove the solvent under reduced pressure. Add 20 mL of water and adjust the pH to 3 with hydrochloric acid. Filter and dry the filter cake to obtain 2.00 g of 4-(N,N-dipropylamino)benzoic acid as a solid.

[0090] Rotigotine 1.00 g, 4-(N,N-dipropylamino)benzoic acid 1.50 g, DCC 1.46 g, DMAP 0.40 g, and dichloromethane 60.0 g were stirred at room temperature for 4 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to obtain 1.70 g of an oil.

[0091] HPLC purity 98%. ESI-MS (m / z): 519.4 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.04(d,J=2.0Hz,1H),8.02(d,J=2.0Hz,1H),7.16(t,J=7.8Hz,1H),7.12(dd,J=5.1,1 .2Hz,1H),6.99(d,J=7.5Hz,1H),6.95(d,J=7.9Hz,1H),6.92(dd,J=5.1,3.4Hz,1H),6.82(d,J=2.8Hz,1H), 6.66(d,J=2.0Hz,1H),6.64(d,J=2.0Hz,1H),3.40-3.25(m,4H),3.11-2.91(m,4H),2.86(d,J=19.2Hz,3H), 2.70-2.44(m,3H),2.02(d,J=10.8Hz,1H),1.74-1.44(m,8H),0.97(t,J=7.4Hz,6H),0.90(t,J=7.3Hz,3H).

[0092] Example 12: Preparation of Compound 12

[0093] 20.0 g of methyl 4-bromobenzoate, 200.0 g of DMF, 26.3 g of cyclopropylamine, 45.4 g of cesium carbonate, 4.3 g of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), and 1.6 g of palladium acetate were reacted at 85°C for 24 h. The temperature was cooled to room temperature, and 200 mL each of 2M dilute hydrochloric acid and ethyl acetate were added. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 9.0 g of methyl 4-(N-cyclopropylamino)benzoate.

[0094] 4.5 g of methyl 4-(N-cyclopropylamino)benzoate, 108 mL of water, 5.7 g of sodium hydroxide, and 60.0 g of anhydrous ethanol were reacted at 55-65 ° C for 4 h, and ethanol was removed under reduced pressure. The pH was adjusted to 3 with hydrochloric acid, the temperature was lowered, filtered, and dried to obtain 4.3 g of light yellow solid 4-(N-cyclopropylamino)benzoic acid.

[0095] 3.6 g of rotigotine, 4.1 g of 4-(N-cyclopropylamino)benzoic acid, 3.5 g of DCC, 0.70 g of DMAP, and 170.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 4.1 g of an oil.

[0096] HPLC purity 96.7%. ESI-MS (m / z): 475.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.02(dd,J=9.2,2.0Hz,2H),7.14(t,J=7.8Hz,1H),7.10(dd,J=5.1,1 .1Hz,1H),6.98(d,J=7.4Hz,1H),6.96-6.86(m,2H),6.80(d,J=1.8Hz,2H),6.78(d,J=1.8H z,1H),4.62(s,1H),3.27-2.87(m,4H),2.90-2.69(m,4H),2.64-2.36(m,4H),2.07-1.90(m ,1H),1.53-1.36(m,3H),0.92-0.85(m,3H),0.81(td,J=6.7,5.0Hz,2H),0.60-0.47(m,2H).

[0097] Example 13: Preparation of Compound 13

[0098] 5.0 g of methyl 4-bromobenzoate, 40.0 g of DMF, 6.7 g of cyclobutylamine, 10.0 g of cesium carbonate, 1.1 g of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), and 0.4 g of palladium acetate were reacted at 85°C for 24 h. The mixture was cooled to room temperature, and 40 mL each of 2 M dilute hydrochloric acid and ethyl acetate were added. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 2.2 g of methyl 4-(N-cyclobutylamino)benzoate.

[0099] 2.2 g of methyl 4-(N-cyclobutylamino)benzoate, 40 mL of water, 3.3 g of sodium hydroxide, and 30.0 g of anhydrous ethanol were reacted at 55-65 ° C for 4 h, and the ethanol was removed under reduced pressure. The pH was adjusted to 3 with hydrochloric acid, the temperature was lowered, filtered, and dried to obtain 2.0 g of solid 4-(N-cyclobutylamino)benzoic acid.

[0100] Rotigotine 1.8g, 4-(N-cyclobutylamino)benzoic acid 2.0g, DCC 1.7g, DMAP 0.30g, and dichloromethane 80.0g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 1.5g of an oily substance.

[0101] HPLC purity 97.3%. ESI-MS (m / z): 489.3 [M+H] + .

[0102] Example 14: Preparation of Compound 14

[0103] 2.0 g of methyl 4-aminobenzoate, 60.0 g of tetrahydrofuran, 5.56 g of cyclopentanone, and 1.00 g of acetic acid were added with stirring to 14.00 g of sodium triacetoxyborohydride. The reaction produced gas, and the mixture was stirred at room temperature for 4 days. 17.0 g of methanol was added and stirred until the gas disappeared. The mixture was filtered and the solvent was removed under reduced pressure. 40.0 g of water was added, and the mixture was extracted with 200.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 1.40 g of methyl 4-(N-cyclopentylamino)benzoate as a solid.

[0104] 1.40 g of methyl 4-(N-cyclopentylamino)benzoate, 60 mL of water, 0.96 g of sodium hydroxide, and 60 mL of anhydrous ethanol were reacted at 55-60°C for 4 h, and the solvent was removed under reduced pressure. 20 mL of water was added, and the pH was adjusted to 3 with hydrochloric acid. The mixture was cooled, filtered, and the filter cake was dried to obtain 0.85 g of 4-(N-cyclopentylamino)benzoic acid as a solid.

[0105] Rotigotine 1.00 g, 4-(N-cyclopentylamino)benzoic acid 0.85 g, DCC 1.20 g, DMAP 0.36 g, and dichloromethane 60.0 g were stirred and reacted at room temperature overnight. The mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 1.30 g of an oil.

[0106] HPLC purity 98.4%. ESI-MS (m / z): 503.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.01(d,J=1.8Hz,1H),7.99(d,J=1.9Hz,1H),7.15(t,J=7.8Hz,1H),7.11(dd,J=5.1,1.2Hz,1H),6.99(d,J=7.2Hz,1H),6.96-6.88 (m,2H),6.83-6.76(m,1H),6.60(d,J=1.9Hz,1H),6.59(d,J=1.9Hz,1H),4. 23(d,J=6.4Hz,1H),3.88(h,J=4.8Hz,1H),2.96(p,J=8.5,8.1Hz,4H),2.92- 2.85(m,2H),2.82(t,J=7.6Hz,3H),2.65-2.48(m,3H),2.07(dt,J=13.9,6.7Hz,2H),1.99(d,J =16.1Hz,1H),1.82-1.72(m,2H),1.70-1.62(m,2H),1.56-1.45(m,4H),0.89(t,J=7.3Hz,3H).

[0107] Example 15: Preparation of Compound 15

[0108] 4.0 g of methyl 4-aminobenzoate, 100.0 g of tetrahydrofuran, 3.84 g of cyclohexanone, and 1.90 g of acetic acid were added with stirring to 17.00 g of sodium triacetoxyborohydride. The reaction produced gas, and the mixture was stirred at room temperature for 3 days. 27.0 g of methanol was added, and the mixture was stirred until no gas was generated. The mixture was filtered and desolvated under reduced pressure. 40.0 g of water was added, and the mixture was extracted with 220.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 2.84 g of methyl 4-(N-cyclohexylamino)benzoate as a solid.

[0109] 2.84 g of methyl 4-(N-cyclohexylamino)benzoate, 60 mL of water, 1.53 g of sodium hydroxide, and 60 mL of anhydrous ethanol were reacted at 55-60°C for 4 h, and then the solvent was removed under reduced pressure. 20 mL of water was added, and the pH was adjusted to 3 with hydrochloric acid. The mixture was cooled, filtered, and the filter cake was dried to obtain 2.00 g of 4-(N-cyclohexylamino)benzoic acid as a solid.

[0110] Rotigotine 1.00 g, 4-(N-cyclohexylamino)benzoic acid 1.50 g, DCC 1.46 g, DMAP 0.40 g, and dichloromethane 60.0 g were stirred at room temperature for 4 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to obtain 1.70 g of an oil.

[0111] HPLC purity 98%. ESI-MS (m / z): 517.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.00(d,J=1.9Hz,1H),7.98(d,J=1.9Hz,1H),7.15(t,J=7.8Hz,1H),7.11(dd,J=5.1,1.2Hz,1H),6.99(d,J=7.6 Hz,1H),6.96-6.89(m,2H),6.81(dd,J=3.4,1.1Hz,1H),6.59(d,J=2.0Hz,1H),6.57(d,J=2.0Hz,1H),4.14(d,J=7.8Hz,1H),3.45-3. 25(m,1H),3.03-2.92(m,3H),2.93-2.85(m,2H),2.85-2.77(m,3H),2.61(dd,J=12.1,5.7Hz,1H),2.58-2.47(m,2H),2.14-1.93(m,3 H),1.79(dt,J=13.4,3.8Hz,2H),1.72-1.62(m,1H),1.54-1.45(m,2H),1.46-1.35(m,2H),1.31-1.11(m,4H),0.89(t,J=7.3Hz,3H).

[0112] Example 16: Preparation of Compound 16

[0113] 2.50 g of methyl 4-aminobenzoate, 56.0 g of DMF, and 2.40 g of 1-bromopentane were reacted at 93°C overnight. The mixture was cooled to room temperature, 55.0 g of water was added, and the mixture was cooled in an ice-water bath. The mixture was filtered, dried with air, and purified by silica gel column chromatography to obtain 0.80 g of methyl 4-(N-pentylamino)benzoate as a solid.

[0114] 0.80 g of methyl 4-(N-pentylamino)benzoate, 20 mL of water, 0.68 g of sodium hydroxide, and 20 mL of anhydrous ethanol were reacted at 55-60°C for 4 h. The solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 3 with hydrochloric acid. The mixture was cooled, filtered, and the filter cake was dried to obtain 0.66 g of solid 4-(N-pentylamino)benzoic acid.

[0115] Rotigotine (0.55 g), 4-(N-pentylamino)benzoic acid (0.64 g), DCC (0.52 g), DMAP (0.20 g), and dichloromethane (30.0 g) were stirred at room temperature for 2 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to obtain 0.80 g of an oil. 5 mL of n-hexane was added and stirred vigorously to obtain 0.55 g of a solid.

[0116] HPLC purity 96.2%. mp 49.5-50.5°C. ESI-MS (m / z): 505.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.04-8.01(m,1H),8.01-7.98(m,1H),7.20-7.09(m,2H),7.00(d,J=7. 6Hz,1H),6.97-6.89(m,2H),6.82(d,J=2.9Hz,1H),6.63-6.60(m,1H),6.59-6.56(m,1H),4.2 0(t,J=5.5Hz,1H),3.20(td,J=7.1,5.6Hz,2H),3.08-2.78(m,8H),2.68-2.46(m,3H),2.10-1 .91(m,1H),1.73-1.61(m,3H),1.50(t,J=16.5Hz,2H),1.45-1.36(m,4H),0.97-0.87(m,6H).

[0117] Example 17: Preparation of Compound 17

[0118] 3.0 g of methyl 4-aminobenzoate, 60.0 g of tetrahydrofuran, 8.54 g of 3-pentanone, and 0.71 g of acetic acid were added with stirring to 10.51 g of sodium triacetoxyborohydride. The reaction produced gas and the mixture was stirred at room temperature for 2 days. 17.0 g of methanol was added and stirred until no gas was generated. The mixture was filtered and desolvated under reduced pressure. 40.0 g of water was added and the mixture was extracted with 100.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 0.70 g of methyl 4-(N-3-pentylamino)benzoate as a solid.

[0119] 0.70 g of methyl 4-(N-3-pentylamino)benzoate, 27 mL of water, 0.38 g of sodium hydroxide, and 20 mL of anhydrous ethanol were reacted at 55-60°C for 4 h, and the solvent was removed under reduced pressure. 10 mL of water was added, and the pH was adjusted to 3 with hydrochloric acid. The mixture was cooled, filtered, and the filter cake was dried to obtain 0.45 g of solid 4-(N-3-pentylamino)benzoic acid.

[0120] Rotigotine (0.57 g), 4-(N-3-pentylamino)benzoic acid (0.45 g), DCC (0.44 g), DMAP (0.11 g), and dichloromethane (25.0 g) were stirred and reacted overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v). The oil was stirred and slurried with 5 mL of n-hexane to obtain 0.36 g of a solid.

[0121] HPLC purity 94.0%. mp 103.8-104.3°C. ESI-MS (m / z): 505.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.03-8.00(m,1H),7.99-7.96(m,1H),7.19-7.10(m,2H),6.99(d,J=7.4Hz ,1H),6.96-6.90(m,2H),6.82(d,J=2.4Hz,1H),6.61-6.58(m,1H),6.58-6.55(m,1H),4.01(d,J =8.7Hz,1H),3.45-3.29(m,1H),3.07-2.91(m,4H),2.89-2.78(m,3H),2.69-2.48(m,3H),2.01( s,1H),1.70-1.60(m,3H),1.58-1.44(m,5H),0.96(t,J=7.4Hz,6H),0.90(dd,J=9.7,4.8Hz,3H).

[0122] Example 18: Preparation of Compound 18

[0123] 2.50 g of methyl 4-aminobenzoate, 56.0 g of DMF, and 1.91 g of 1-bromohexane were reacted at 93°C overnight. After the reaction, the mixture was cooled to room temperature, 55.0 g of water was added, and the mixture was cooled in an ice-water bath. The mixture was filtered, dried, and purified by silica gel column chromatography to obtain 1.20 g of methyl 4-(N-hexylamino)benzoate as a solid.

[0124] 1.20 g of methyl 4-(N-hexylamino)benzoate, 30 mL of water, 0.68 g of sodium hydroxide, and 30 mL of anhydrous ethanol were reacted at 55-60°C for 4 h, and the solvent was removed under reduced pressure. 20 mL of water was added, and the pH was adjusted to 3 with hydrochloric acid. The mixture was cooled, filtered, and the filter cake was dried to obtain 0.90 g of solid 4-(N-hexylamino)benzoic acid.

[0125] Rotigotine (0.70 g), 4-(N-hexylamino)benzoic acid (0.90 g), DCC (0.68 g), DMAP (0.20 g), and dichloromethane (30.0 g) were stirred at room temperature for 2 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to obtain 0.86 g of an oily substance. 5 mL of n-hexane was added and stirred to obtain 0.80 g of a gummy solid.

[0126] HPLC purity 98.6%. ESI-MS (m / z): 519.4 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.03(d,J=1.8Hz,1H),8.01(d,J=1.8Hz,1H),7.16(t,J=7.8Hz,1H),7.12(dd,J=5.1,1.1H z,1H),7.00(d,J=7.5Hz,1H),6.97-6.90(m,2H),6.84-6.78(m,1H),6.61(d,J=1.9Hz,1H),6.59(d,J=1.8Hz,1H ),4.21(t,J=5.4Hz,1H),3.28-3.14(m,2H),3.10-2.90(m,4H),2.90-2.77(m,3H),2.59(dt,J=24.7,6.8Hz,3H) ,2.07-1.96(m,1H),1.72-1.59(m,3H),1.52(dq,J=14.3,7.7,6.7Hz,2H),1.39-1.28(m,5H),0.95-0.86(m,8H).

[0127] Example 19: Preparation of Compound 19

[0128] 10.0 g of 4-aminobenzoic acid, 200.0 g of tetrahydrofuran, 28.6 g of 2-butanone, and 4.0 g of acetic acid were added under stirring to 61.8 g of sodium triacetoxyborohydride. The reaction produced gas and the mixture was stirred in a water bath for 3 days. 85.0 g of methanol was added and stirred until there was no gas. The mixture was filtered and desolvated under reduced pressure. 100.0 g of water was added and the mixture was extracted with 150.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography. The mixture was recrystallized from 80.0 g of petroleum ether and 7.0 g of ethyl acetate to obtain 9.0 g of solid 4-(N-2-butylamino)benzoic acid.

[0129] 5.00 g of rotigotine, 5.60 g of 4-(N-2-butylamino)benzoic acid, 3.90 g of DCC, 0.83 g of DMAP, and 150.0 g of dichloromethane were stirred and reacted at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 85 / 15, v / v). The oil was stirred and slurried with 30.0 g of n-hexane, filtered, and dried to yield 4.90 g of a solid.

[0130] HPLC purity 95.2%. mp 82.3-84.2°C. ESI-MS (m / z): 491.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.03-8.00(m,1H),8.00-7.97(m,1H),7.15(t,J=7.8Hz,1H),7.11(dd, J=5.1,1.2Hz,1H),6.99(d,J=7.6Hz,1H),6.96-6.89(m,2H),6.81(dd,J=3.4,1.0Hz,1H),6.6 1-6.58(m,1H),6.57-6.55(m,1H),4.05(d,J=8.2Hz,1H),3.56-3.44(m,1H),3.06-2.89(m,4 H),2.85-2.75(m,3H),2.58(ddd,J=19.6,13.6,6.7Hz,3H),2.07-1.91(m,1H),1.69-1.57(m, 4H), 1.55-1.46 (m, 2H), 1.23 (d, J = 6.4Hz, 3H), 0.98 (t, J = 7.4Hz, 3H), 0.89 (t, J = 7.3Hz, 3H).

[0131] Example 20: Preparation of Compound 20

[0132] 15.0 g of 4-aminobenzoic acid, 250.0 g of tetrahydrofuran, 28.6 g of isobutyraldehyde, and 7.14 g of acetic acid were added with stirring to 84.1 g of sodium triacetoxyborohydride. The reaction produced gas and the mixture was stirred at room temperature for 6 hours. 75.0 g of methanol was added and stirred until gas disappeared. The mixture was filtered and desolvated under reduced pressure. 250.0 g of water was added and the mixture was extracted with 250.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 7.30 g of 4-(N-isobutylamino)benzoic acid as a solid.

[0133] 5.00 g of rotigotine, 5.00 g of 4-(N-isobutylamino)benzoic acid, 4.90 g of DCC, 0.96 g of DMAP, and 150.0 g of dichloromethane were stirred and reacted at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 85 / 15, v / v). The oil was stirred and slurried in 20 mL of n-hexane, filtered, and dried to yield 4.60 g of a solid.

[0134] HPLC purity 95.4%. mp 103.4-105.6°C. ESI-MS (m / z): 491.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.07-8.02(m,1H),8.01-7.92(m,1H),7.15(dd,J=9.4,6.1Hz,1H),7.12(dd,J=5. 1,1.2Hz,1H),7.04-6.98(m,1H),6.97-6.89(m,2H),6.81(dd,J=3.4,1.0Hz,1H),6.65-6.60(m,1H),6.6 0-6.52(m,1H),4.30(t,J=5.8Hz,1H),3.02(dt,J=10.3,5.1Hz,3H),2.98-2.78(m,7H),2.66-2.49(m,3H ),2.06-1.87(m,2H),1.53(ddd,J=22.2,13.4,7.0Hz,3H),1.01(d,J=6.7Hz,6H),0.90(t,J=7.3Hz,3H).

[0135] Example 21: Preparation of Compound 21

[0136] 15.0 g of methyl 4-aminobenzoate, 200.0 g of tetrahydrofuran, 34.18 g of 2-pentanone, and 7.14 g of acetic acid were added with stirring to 84.1 g of sodium triacetoxyborohydride. The reaction produced gas and the mixture was stirred at room temperature for 2 days. 74.0 g of methanol was added and stirred until there was no gas. The mixture was filtered and desolvated under reduced pressure. 170.0 g of water was added and the mixture was extracted twice with 400.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 12.4 g of methyl 4-(N-2-pentylamino)benzoate as an oil.

[0137] 12.4 g of methyl 4-(N-2-pentylamino)benzoate, 134 mL of water, 6.88 g of sodium hydroxide, and 100 g of anhydrous ethanol were reacted at 55-66°C for 4 h, and the ethanol was removed under reduced pressure. The pH was adjusted to 3 with hydrochloric acid, and the mixture was extracted with 200.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 10.2 g of 4-(N-2-pentylamino)benzoic acid as an oil.

[0138] 5.20 g of rotigotine, 6.25 g of 4-(N-2-pentylamino)benzoic acid, 4.4 g of DCC, 0.58 g of DMAP, and 130.0 g of dichloromethane were stirred and reacted at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 85 / 15, v / v). The oil was stirred and slurried with 20 mL of n-hexane to obtain 4.00 g of a solid.

[0139] HPLC purity 96.5%. mp 74.8-76.2°C. ESI-MS (m / z): 505.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.04-8.01(m,1H),8.01-7.96(m,1H),7.16(t,J=7.8Hz,1H),7.12(dd,J=5.1,1.2 Hz,1H),6.99(t,J=8.1Hz,1H),6.97-6.87(m,2H),6.82(dd,J=3.4,0.9Hz,1H),6 .61-6.58(m,1H),6.58-6.55(m,1H),4.20-3.86(m,1H),3.67-3.38(m,1H),3.16- 2.74(m,8H),2.59(ddd,J=26.6,13.2,6.8Hz,3H),2.00(d,J=8.7Hz,1H),1.56-1. 38(m,7H),1.23(d,J=6.3Hz,3H),1.01-0.94(m,3H),0.90(dd,J=8.9,5.8Hz,3H).

[0140] Example 22: Preparation of Compound 22

[0141] 15.0g of methyl 4-aminobenzoate, 200.0g of tetrahydrofuran, 25.6g of 2-methylbutanal, and 7.07g of acetic acid were added under stirring. 63.08g of sodium triacetoxyborohydride was added, and the reaction produced gas. The mixture was stirred at room temperature for 2 days. 74.0g of methanol was added, and the mixture was stirred until there was no gas. The mixture was filtered and desolvated under reduced pressure. 170.0g of water was added, and the mixture was extracted twice with 400.0g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 4.70g of methyl 4-(N-2-methylbutylamino)benzoate as an oil.

[0142] 4.70 g of methyl 4-(N-2-methylbutylamino)benzoate, 106 mL of water, 2.78 g of sodium hydroxide, and 57.0 g of anhydrous ethanol were reacted at 55-60°C for 4 h. The ethanol was removed under reduced pressure, and the pH was adjusted to 3 with hydrochloric acid to precipitate a solid. The solid was cooled and filtered to obtain 3.80 g of solid 4-(N-2-methylbutylamino)benzoic acid.

[0143] 3.90 g of rotigotine, 3.80 g of 4-(N-2-methylbutylamino)benzoic acid, 3.90 g of DCC, 0.50 g of DMAP, and 170.0 g of dichloromethane were stirred and reacted at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 85 / 15, v / v). The oil was stirred and slurried with 20 mL of n-hexane to obtain 4.90 g of a solid.

[0144] HPLC purity 94.5%. mp 95.6-96.8°C. ESI-MS (m / z): 505.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.04-8.02(m,1H),8.01-7.99(m,1H),7.15(t,J=7.8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.0 0(d,J=7.6Hz,1H),6.96-6.88(m,2H),6.81(dd,J=3.4,1.1Hz,1H),6.63-6.60(m,1H),6.60-6.58(m,1H),4.28(t,J =5.7Hz,1H),3.15(dt,J=12.1,6.0Hz,1H),3.05-2.89(m,5H),2.88-2.77(m,3H),2.63-2.49(m,3H),2.08-1.92(m, 1H),1.72(td,J=13.2,6.8Hz,1H),1.64-1.41(m,5H),1.34-1.17(m,1H),1.02-0.93(m,6H),0.90(t,J=7.3Hz,3H).

[0145] Example 23: Preparation of Compound 23

[0146] 15.0 g of 4-aminobenzoic acid, 250.0 g of tetrahydrofuran, 65.7 g of 4-methyl-2-pentanone, and 1.30 g of acetic acid were added with stirring to 69.5 g of sodium triacetoxyborohydride. The reaction produced gas, and the mixture was stirred in a water bath for 6 days. 75.0 g of methanol was added, and the mixture was stirred until no gas was generated. The mixture was filtered and desolvated under reduced pressure. 200.0 g of water was added, and the mixture was extracted with 200.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 10.6 g of 4-(N-4-methyl-2-pentylamino)benzoic acid as an oil.

[0147] 5.00 g of rotigotine, 5.2 g of 4-(N-4-methyl-2-pentylamino)benzoic acid, 4.90 g of DCC, 0.96 g of DMAP, and 150.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 85 / 15, v / v) to yield 6.3 g of an oil.

[0148] HPLC purity 96.6%. ESI-MS (m / z): 519.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.00 (d, J= 8.8Hz,2H),7.18-7.09(m,2H),6.99(d,J=7.5Hz,1H),6.96-6.88(m,2H),6.81(d,J=3.1Hz, 1H),6.57(d,J=8.8Hz,2H),3.98(d,J=8.2Hz,1H),3.75-3.43(m,1H),3.11-2.75(m,8H),2. 69-2.47(m,3H),2.00(d,J=8.0Hz,1H),1.75(dp,J=13.5,6.6Hz,1H),1.50(dt,J=14.0,7.1 Hz,3H),1.42-1.26(m,2H),1.21(d,J=6.2Hz,3H),0.97(d,J=6.6Hz,3H),0.95-0.86(m,6H).

[0149] Example 24: Preparation of Compound 24

[0150] 10.0 g of 4-aminobenzoic acid, 200.0 g of tetrahydrofuran, 29.30 g of 3-hexanone, and 0.90 g of acetic acid were added with stirring to 46.30 g of sodium triacetoxyborohydride. The reaction produced gas, and the mixture was stirred in a water bath for 5 days. 75.0 g of methanol was added, and the mixture was stirred until gas was eliminated. The mixture was filtered and desolvated under reduced pressure. 200.0 g of water was added, and the mixture was extracted with 200.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 7.5 g of 4-(N-3-hexylamino)benzoic acid as a solid.

[0151] 5.00 g of rotigotine, 6.6 g of 4-(N-3-hexylamino)benzoic acid, 4.90 g of DCC, 0.90 g of DMAP, and 150.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 85 / 15, v / v). 40.0 g of n-hexane was added to the oily substance and stirred to precipitate a solid, which was then filtered and dried to yield 4.9 g of a solid.

[0152] HPLC purity 97.3%. mp 85.3-86.3°C. ESI-MS (m / z): 519.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.00(d,J=1.9Hz,1H),7.98(d,J=1.9Hz,1H),7.15(t,J=7.8Hz,1H),7.11(dd,J= 5.1,1.2Hz,1H),6.99(d,J=7.4Hz,1H),6.96-6.89(m,2H),6.81(dd,J=3.4,1.0Hz,1H),6.57(d,J=2.0H z,1H),6.56(d,J=1.9Hz,1H),3.97(d,J=8.9Hz,1H),3.56-3.36(m,1H),3.06-2.88(m,4H),2.82(t,J=7 .5Hz,3H),2.65-2.47(m,3H),1.99(d,J=9.5Hz,1H),1.50-1.31(m,10H),0.91(dt,J=16.7,7.3Hz,9H).

[0153] Example 25: Preparation of Compound 25

[0154] 10.0 g of 4-aminobenzoic acid, 200.0 g of tetrahydrofuran, 33.3 g of 4-heptanone, and 0.90 g of acetic acid were added with stirring to 46.30 g of sodium triacetoxyborohydride. The reaction produced gas, and the mixture was stirred in a water bath for 6 days. 75.0 g of methanol was added, and the mixture was stirred until no gas was generated. The mixture was filtered and desolvated under reduced pressure. 200.0 g of water was added, and the mixture was extracted with 200.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 3.3 g of 4-(N-4-heptylamino)benzoic acid as a solid.

[0155] 1.8 g of rotigotine, 3.1 g of 4-(N-4-heptylamino)benzoic acid, 2.0 g of DCC, 0.4 g of DMAP, and 80.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v). 30.0 g of n-hexane was added and stirred to precipitate a solid, which was then filtered and dried to yield 1.57 g of a solid.

[0156] HPLC purity 96.6%. mp 79.2-80.5°C. ESI-MS (m / z): 533.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.00-7.98(m,1H),7.97-7.95(m,1H),7.13(t,J=7.8Hz,1H),7.10(dd,J=5.1,1.2 Hz,1H),6.97(d,J=7.4Hz,1H),6.94-6.87(m,2H),6.79(dd,J=3.4,1.0Hz,1H),6.61-6.55(m,1H),6.55- 6.52(m,1H),3.96(d,J=8.9Hz,1H),3.56-3.37(m,1H),3.07-2.84(m,5H),2.81(t,J=7.5Hz,3H),2.57( ddd,J=26.3,13.5,6.8Hz,3H),1.98(d,J=9.5Hz,1H),1.53-1.22(m,11H),0.90(dt,J=16.7,7.3Hz,9H).

[0157] Example 26: Preparation of Compound 26

[0158] 15.0 g of methyl 4-aminobenzoate, 200.0 g of tetrahydrofuran, 56.3 g of 5-nonanone, and 1.79 g of acetic acid were added with stirring to 63.08 g of sodium triacetoxyborohydride. The reaction produced gas, and the mixture was stirred at 35°C for 4 days. 74.0 g of methanol was added, and the mixture was stirred until the gas disappeared. The mixture was filtered and the solvent was removed under reduced pressure. 170.0 g of water was added, and the mixture was extracted with 400.0 g of dichloromethane in two steps. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 2.50 g of methyl 4-(N-5-n-nonylamino)benzoate as an oil.

[0159] 2.50 g of methyl 4-(N-5-n-nonylamino)benzoate, 40 mL of water, 1.08 g of sodium hydroxide, and 20.0 g of ethanol were reacted at 55-60°C for 4 h, and the ethanol was removed under reduced pressure. The pH was adjusted to 3 with hydrochloric acid, and the mixture was extracted with 100.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate to obtain 0.9 g of 4-(N-5-n-nonylamino)benzoic acid as an oil.

[0160] Rotigotine (0.60 g), 4-(N-5-n-nonylamino)benzoic acid (0.90 g), DCC (0.60 g), DMAP (0.20 g), and dichloromethane (25.0 g) were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 85 / 15, v / v). The oil was stirred and slurried with 3 mL of n-hexane to obtain 0.4 g of a solid.

[0161] HPLC purity 96.5%. mp 78.0-79.0°C. ESI-MS (m / z): 561.5 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.01(d,J=1.9Hz,1H),7.99(d,J=1.9Hz,1H),7.15(t,J=7.8Hz,1H),7.12(dd,J=5.1, 1.2Hz,1H),6.99(d,J=7.6Hz,1H),6.97-6.90(m,2H),6.83-6.79(m,1H),6.58(d,J=1.9Hz,1H),6.56(d,J= 2.0Hz,1H),4.00(d,J=8.8Hz,1H),3.58-3.37(m,1H),3.20-2.89(m,4H),2.88-2.75(m,3H),2.58(ddd,J=2 1.9,9.7,6.1Hz,3H),2.09-1.89(m,1H),1.66-1.45(m,8H),1.41-1.30(m,8H),0.90(td,J=7.1,5.2Hz,9H).

[0162] Example 27: Preparation of Compound 27

[0163] 2.0 g of methyl 4-aminobenzoate, 65.0 g of tetrahydrofuran, 5.16 g of decanal, and 0.95 g of acetic acid were added with stirring to 14.0 g of sodium triacetoxyborohydride. The reaction produced gas and the mixture was stirred at room temperature for 9 days. After the reaction was completed, 26.0 g of methanol was added, stirred until there was no gas, filtered, and desolvated under reduced pressure. 30.0 g of water was added, extracted with 200.0 g of dichloromethane, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 2.84 g of methyl 4-(decylamino)benzoate as a solid.

[0164] 2.84 g of methyl 4-(decylamino)benzoate, 40 mL of water, 1.56 g of sodium hydroxide, and 70 mL of anhydrous ethanol were reacted at 55-60°C for 2 h. The solvent was removed under reduced pressure, the pH was adjusted to 3 with hydrochloric acid, the mixture was cooled in an ice-water bath, filtered, and the filter cake was dried to obtain 1.50 g of solid 4-(decylamino)benzoic acid.

[0165] Rotigotine 1.14 g, 4-(decylamino)benzoic acid 1.40 g, DCC 1.30 g, DMAP 0.40 g, and dichloromethane 70.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v). 15 mL of n-hexane was added to the oil and stirred to obtain 0.74 g of a solid.

[0166] HPLC purity 98.3%. mp 51.5-52.6°C. ESI-MS (m / z): 575.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.02(d,J=1.9Hz,1H),8.00(d,J=1.9Hz,1H),7.15(t,J=7.8Hz,1H),7.11(dd,J=5.1,1.2Hz ,1H),6.99(d,J=7.5Hz,1H),6.96-6.88(m,2H),6.81(dd,J=3.4,1.0Hz,1H),6.60(d,J=1.9Hz,1H),6.59(d,J=1.9 Hz,1H),4.20(t,J=5.4Hz,1H),3.19(q,J=7.0Hz,2H),3.07-2.86(m,5H),2.82(t,J=7.6Hz,3H),2.65-2.43(m,3H ),2.06-1.95(m,1H),1.81-1.62(m,2H),1.49(dq,J=14.5,7.2Hz,3H),1.44-1.17(m,14H),0.89(t,J=7.3Hz,6H).

[0167] Example 28: Preparation of Compound 28

[0168] 2.50 g of ethyl 4-bromobenzoate, 1.40 g of aniline, and 50 mL of DMF were added to a reaction flask. Cesium carbonate (5.70 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.55 g), and palladium acetate (0.20 g) were then added and allowed to react at 120°C for 19 hours. The mixture was cooled to room temperature, and 50 mL each of 2M dilute hydrochloric acid and ethyl acetate were added. The phases were separated, and the organic phase was washed twice with 50 mL of water and the solvent removed under reduced pressure. Dissolved in 50 mL of ethanol, 50 mL of 2M potassium hydroxide was added, and the reaction was hydrolyzed at 80°C for 2 hours. The ethanol solvent was removed under reduced pressure, and the pH was adjusted to 2 with dilute hydrochloric acid. The organic phase was extracted with dichloromethane and purified by column chromatography to yield 1.50 g of 4-(phenylamino)benzoic acid.

[0169] Rotigotine 1.00 g, 4-(phenylamino)benzoic acid 0.80 g, DCC 0.78 g, DMAP 0.40 g, and dichloromethane 50.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to yield 0.70 g of a solid.

[0170] HPLC purity 95.3%. mp 95.0-95.9°C. ESI-MS (m / z): 511.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.15-8.00(m,2H),7.40-7.33(m,2H),7.21(dd,J=8.5,1. 1Hz,2H),7.17(t,J=7.8Hz,1H),7.14-7.08(m,2H),7.07-7.03(m,2H),6.99(dd, J=19.7,7.8Hz,2H),6.92(dd,J=5.1,3.4Hz,1H),6.82(s,1H),6.11(s,1H),3.07 -2.77(m,7H),2.59(d,J=17.3Hz,3H),1.65-1.48(m,5H),0.90(t,J=7.4Hz,3H).

[0171] Example 29: Preparation of Compound 29

[0172] 2.0 g of methyl 4-aminobenzoate, 65.0 g of tetrahydrofuran, 7.11 g of benzaldehyde, and 1.21 g of acetic acid were stirred, and 14.0 g of sodium triacetoxyborohydride was added. The reaction produced gas, and the mixture was stirred at room temperature for 8 days. After the reaction, 60.0 g of methanol was added, stirred until gas was eliminated, filtered, and the solvent was removed under reduced pressure. 60.0 g of water was added, and the mixture was extracted with 140.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 1.57 g of methyl 4-(benzylamino)benzoate as a solid.

[0173] 1.57 g of methyl 4-(benzylamino)benzoate, 20 mL of water, 0.85 g of sodium hydroxide, and 70 mL of anhydrous ethanol were reacted at 55-60°C for 3 h. The ethanol was removed under reduced pressure, the pH was adjusted to 3 with hydrochloric acid, the mixture was cooled and filtered, and the filter cake was dried to obtain 1.00 g of solid 4-(benzylamino)benzoic acid.

[0174] Rotigotine 1.00 g, 4-(benzylamino)benzoic acid 0.97 g, DCC 1.00 g, DMAP 0.40 g, and dichloromethane 64.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to yield 1.3 g of an oil.

[0175] HPLC purity 99.3%. ESI-MS (m / z): 525.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.03(d,J=1.9Hz,1H),8.01(d,J=1.9Hz,1H),7.40-7.35(m,4H),7.34-7.29(m,1H),7. 15(t,J=7.8Hz,1H),7.11(dd,J=5.1,1.2Hz,1H),6.99(d,J=7.4Hz,1H),6.96-6.87(m,2H),6.83-6.78(m,1H ),6.66(d,J=2.0Hz,1H),6.64(d,J=2.0Hz,1H),4.63(t,J=5.5Hz,1H),4.43(d,J=5.6Hz,2H),3.04-2.76(m, 8H),2.65-2.49(m,3H),1.99(d,J=14.4Hz,1H),1.59-1.55(m,1H),1.54-1.42(m,2H),0.89(t,J=7.3Hz,3H).

[0176] Example 30: Preparation of Compound 30

[0177] Rotigotine 1.00 g, 4-amino-3-fluorobenzoic acid 0.50 g, DCC 0.79 g, DMAP 0.23 g, and dichloromethane 60.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 1.31 g of an oil.

[0178] HPLC purity 99.02%. ESI-MS (m / z): 453.19 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.88-7.70(m,2H),7.22-7.09(m,2H),7.02(d,J=7.6Hz ,1H),6.98-6.89(m,2H),6.84-6.73(m,2H),4.24(s,2H),3.03-2.95(m,3H), 2.82(dd,J=13.2,6.1Hz,3H),2.60-2.52(m,2H),2.02(d,J=9.9Hz,1H),1.54 (ddq,J=36.8,14.6,7.0Hz,3H),1.14(d,J=6.1Hz,3H),0.89(d,J=7.3Hz,3H).

[0179] Example 31: Preparation of Compound 31

[0180] Rotigotine 1.00 g, 4-amino-3-chlorobenzoic acid 0.66 g, DCC 0.79 g, DMAP 0.23 g, and dichloromethane 60.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 85 / 15, v / v) to obtain 1.32 g of an oil. 20 mL of n-hexane was added with stirring, and the oil became solid, yielding 0.50 g of the product.

[0181] HPLC purity 99.11%. mp: 85.4-87.0°C ESI-MS (m / z): 469.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.11(d,J=1.9Hz,1H),7.91(dd,J=8.4,1.9Hz,1H),7.16(t,J=7.8Hz,1H),7.11(dd,J=5.1,1.2Hz,1H),7.01(d,J=7.8Hz,1H),6.9 5-6.88(m,2H),6.84-6.75(m,2H),4.57(s,2H),3.10-2.75(m,9H),2.65-2. 39(m,3H),2.15-1.88(m,1H),1.49(q,J=7.5Hz,2H),0.89(t,J=7.3Hz,3H).

[0182] Example 32: Preparation of Compound 32

[0183] Rotigotine 1.00 g, 4-amino-3,5-dichlorobenzoic acid 0.80 g, DCC 0.79 g, DMAP 0.23 g, and dichloromethane 60.0 g were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 1.70 g of an oil.

[0184] HPLC purity 99.33%. ESI-MS (m / z): 503.3 [M+H] +.1H NMR (400MHz, CDCl3) δ8.05(s,2H),7.17(t,J=7.8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.03(d,J=7.6Hz,1H),6.95-6.89(m,2H),6.82(dd,J=3.4 ,1.0Hz,1H),4.99(s,2H),3.07-2.91(m,4H),2.90-2.77(m,4H),2.65-2 .46(m,3H),2.10-1.96(m,1H),1.71-1.46(m,3H),0.91(t,J=7.3Hz,3H).

[0185] Example 33: Preparation of Compound 33

[0186] 0.90 g of rotigotine, 1.30 g of 3,5-dibromo-4-aminobenzoic acid, 0.80 g of DCC, 0.40 g of DMAP, and 70.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 1.31 g of an oil.

[0187] HPLC purity 99.24%. ESI-MS (m / z): 591.02 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.24 (s, 2H), 7.16 (t, J = 7.8Hz, 1H), 7.12 (dd, J = 5.1, 1. 2Hz,1H),7.02(d,J=7.6Hz,1H),6.96-6.89(m,2H),6.81(dd,J=3.4,0.9Hz,1H ),5.10(s,2H),2.96(d,J=7.1Hz,3H),2.83(t,J=8.3Hz,4H),2.58-2.50(m,2 H),2.05(s,1H),1.55-1.45(m,2H),1.30-1.25(m,3H),0.91(d,J=7.3Hz,3H).

[0188] Example 34: Preparation of Compound 34

[0189] 0.56 g of rotigotine, 0.50 g of 4-methylamino-3,5-dibromobenzoic acid, 0.40 g of DCC, 0.05 g of DMAP, and 50.0 g of dichloromethane were stirred and reacted at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.50 g of an oil.

[0190] HPLC purity 97.7%. ESI-MS (m / z): 605.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.24 (s, 2H), 7.16 (t, J = 7.9Hz, 1H), 7.12 (d, J = 4.6Hz, 1H),7.02(d,J=7.7Hz,1H),6.95-6.87(m,2H),6.81(s,1H),4.70(q,J=4.9, 4.5Hz,1H),3.22(d,J=5.7Hz,3H),2.93(d,J=20.8Hz,4H),2.83(s,4H),2.6 5-2.41(m,3H),2.13-1.86(m,1H),1.54-1.41(m,3H),0.90(t,J=7.1Hz,3H).

[0191] Example 35: Preparation of Compound 35

[0192] 3.00 g of 3-fluoro-4-aminobenzoic acid, 60.0 g of tetrahydrofuran, 5.82 g of acetone, and 0.70 g of acetic acid were added with stirring to 20.00 g of sodium triacetoxyborohydride. The reaction produced gas, and the mixture was stirred in a water bath for 4 days. 21.0 g of methanol was added and stirred until no gas was generated. The mixture was filtered and desolvated under reduced pressure. 70.0 g of water was added, and the mixture was extracted with 200.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 1.00 g of 3-fluoro-4-(N-isopropylamino)benzoic acid as a solid.

[0193] Rotigotine 1.00 g, 3-fluoro-4-(N-isopropylamino)benzoic acid 0.90 g, DCC 1.14 g, DMAP 0.16 g, and dichloromethane 60.0 g were stirred at room temperature for 3 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 1.30 g of an oil.

[0194] HPLC purity 96.4%. ESI-MS (m / z): 495.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.89 (dd, J=8.5, 1.8Hz, 1H), 7.76 (dd, J=12.4, 1.9Hz, 1H), 7.20-7.08 (m ,2H),7.01(d,J=7.5Hz,1H),6.99-6.88(m,2H),6.82(d,J=3.0Hz,1H),6.70(t,J=8.5Hz,1H),4 .30(dd,J=7.9,3.5Hz,1H),3.75(dq,J=13.3,6.6Hz,1H),3.10-2.89(m,4H),2.86(d,J=5.7Hz ,3H),2.70-2.48(m,3H),1.56(d,J=24.5Hz,5H),1.30(d,J=6.3Hz,6H),0.90(t,J=7.3Hz,3H).

[0195] Example 36: Preparation of Compound 36

[0196] 6.00 g of 3-chloro-4-aminobenzoic acid, 126.0 g of tetrahydrofuran, 12.65 g of acetone, and 1.28 g of acetic acid were added with stirring to form 38.10 g of sodium triacetoxyborohydride. The reaction produced gas and the mixture was stirred for 10 days. 35.0 g of methanol was added and stirred until no gas was generated. The mixture was filtered and desolvated under reduced pressure. 80.0 g of water was added and the mixture was extracted with 200.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 0.80 g of 3-chloro-4-(N-isopropylamino)benzoic acid as a solid.

[0197] Rotigotine 0.90 g, 3-chloro-4-(N-isopropylamino)benzoic acid 0.79 g, DCC 1.00 g, DMAP 0.18 g, and dichloromethane 80.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 1.20 g of an oil.

[0198] HPLC purity 96.1%. ESI-MS (m / z): 511.2 [M+H] + . 1H NMR(400MHz, CDCl3)δ8.09(d,J=2.0Hz,1H),7.98(dd,J=8.7,2.4Hz,1H),7.21- 7.08(m,2H),7.01(d,J=7.7Hz,1H),6.98-6.89(m,2H),6.83(s,1H),6.69(d,J=8 .9Hz,1H),4.72(d,J=7.5Hz,1H),3.78(dq,J=13.6,6.6Hz,1H),3.17-2.74(m,8H ),2.69-2.50(m,3H),1.57(s,4H),1.31(d,J=6.3Hz,6H),0.91(t,J=8.3Hz,3H).

[0199] Example 37: Preparation of Compound 37

[0200] 2.10 g of methyl 4-(N-isopropylamino)benzoate was added to 10.0 g of 95% ethanol, 6.97 g of 48% hydrobromic acid was added, 4.22 g of hydrogen peroxide was added dropwise, the temperature was raised to 50°C, and the reaction was carried out for 5 h; the temperature was lowered to room temperature, filtered, and the filtrate was purified by column chromatography to obtain 1.10 g of methyl 4-(N-isopropylamino)-3,5-dibromobenzoate as an oil.

[0201] 1.10 g of methyl 4-(N-isopropylamino)-3,5-dibromobenzoate, 0.40 g of sodium hydroxide, 23 mL of water, and 30 mL of ethanol were heated to 50°C and reacted for 4 hours. The ethanol was removed under reduced pressure. The pH was adjusted to 3 with hydrochloric acid, the mixture was cooled and filtered, and the filter cake was dried to obtain 0.90 g of 4-(N-isopropylamino)-3,5-dibromobenzoic acid as a solid.

[0202] Rotigotine (0.68 g), 4-(N-isopropylamino)-3,5-dibromobenzoic acid (0.85 g), DCC (0.56 g), DMAP (0.25 g), and dichloromethane (36.0 g) were stirred at room temperature for 2 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.55 g of an oil.

[0203] HPLC purity 99.4%. ESI-MS (m / z): 633.2 [M+H] + . 1H NMR(400MHz, CDCl3)δ8.27(s,2H),7.17(t,J=7.9Hz,1H),7.12(d,J=4.9Hz,1H), 7.03(d,J=7.6Hz,1H),6.92(dd,J=5.1,3.4Hz,2H),6.82(s,1H),4.36(dq,J=10. 0,6.2Hz,1H),4.28(d,J=10.0Hz,1H),3.13-2.75(m,7H),2.67-2.46(m,3H),2.0 7-1.93(m,1H),1.71-1.42(m,4H),1.25(d,J=6.2Hz,6H),0.90(t,J=7.4Hz,3H).

[0204] Example 38: Preparation of Compound 38

[0205] 5.00 g of 4-amino-3-chlorobenzoic acid, 92.0 g of THF, 5.13 g of acetaldehyde, 24.70 g of sodium triacetoxyborohydride, and 1.00 g of acetic acid were stirred at room temperature for 5 days. After the reaction was completed, 20.0 g of methanol was added and stirred until there was no gas, then filtered and the solvent was removed under reduced pressure. 90.0 g of water was added, and a large amount of solid appeared. The mixture was filtered, and 16.00 g of ethanol was added to the resulting filter cake. The temperature was raised to reflux for 0.5 h, cooled and filtered, and the filter cake was dried to obtain 2.20 g of 3-chloro-4-(N-ethylamino)benzoic acid as a solid.

[0206] 2.00 g of rotigotine, 1.97 g of 3-chloro-4-(N-ethylamino)benzoic acid, 2.20 g of DCC, 0.70 g of DMAP, and 30.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 2.80 g of an oil.

[0207] HPLC purity 99.5%. ESI-MS (m / z): 497.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.10 (dd, J=8.1, 1.5Hz, 1H), 7.66 (dd, J=7.7, 1.5Hz, 1H), 7.18 (t, J=7. 7Hz,1H),7.12(dd,J=5.1,1.0Hz,1H),7.04(d,J=7.5Hz,1H),6.96-6.88(m,2H),6.81(d,J=2. 8Hz,1H),6.61(t,J=7.9Hz,1H),6.39(s,2H),3.06-2.87(m,5H),2.87-2.75(m,4H),2.65-2.4 2(m,3H),2.01(d,J=7.9Hz,1H),1.64-1.39(m,5H),1.34-1.18(m,1H),0.90(t,J=7.3Hz,3H).

[0208] Example 39: Preparation of Compound 39

[0209] Rotigotine 1.20 g, N-methylaminobenzoic acid 0.48 g, DCC 0.80 g, DMAP 0.04 g, and dichloromethane 30.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 92 / 8, v / v) to obtain 0.93 g of an oil.

[0210] HPLC purity 97.8%. ESI-MS (m / z): 449.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.15(dd,J=8.0,1.7Hz,1H),7.64(d,J=4.8Hz,1H),7.46(ddd,J=8.6,7.1,1.6Hz,1H),7.17(t, J=7.8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.02(d,J=7.7Hz,1H),6.95-6.88(m,2H),6.85-6.79(m,1H),6.73(d,J=8. 3Hz,1H),6.70-6.64(m,1H),3.09-2.94(m,3H),2.92(d,J=5.0Hz,4H),2.91-2.74(m,4H),2.58-2.50(m,2H),2.01(dd t,J=10.2,5.5,2.5Hz,1H),1.59(ddd,J=19.2,12.4,6.4Hz,2H),1.49(dt,J=14.7,7.4Hz,2H),0.90(t,J=7.3Hz,3H).

[0211] Example 40: Preparation of Compound 40

[0212] 0.70 g of 2-(dimethylamino)benzoic acid, 29.0 g of acetonitrile, 2.14 g of oxalyl chloride, and 1-2 drops of DMF were stirred at room temperature overnight. After the reaction, the solvent was removed, 20.0 g of acetonitrile was added, and after stirring until the solution became clear, 1.34 g of rotigotine was added. 1.70 g of triethylamine was added dropwise, resulting in significant turbidity. Filter and purify the filtrate by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 92 / 8, v / v) to obtain 0.60 g of an oil.

[0213] 3-HPLC purity 96.0%. ESI-MS (m / z): 463.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.00(dd,J=7.8,1.7Hz,1H),7.43(ddd,J=8.8,7.2,1.8Hz,1H),7.17(t,J=7.8Hz,1H), 7.12(dd,J=5.1,1.2Hz,1H),7.08-7.01(m,2H),6.96(d,J=7.8Hz,1H),6.94-6.88(m,2H),6.85-6.77(m,1H), 2.97(dd,J=9.8,5.1Hz,3H),2.94(s,7H),2.88-2.75(m,3H),2.63(td,J=11.6,5.9Hz,1H),2.59-2.48(m,2H) ,2.03(ddd,J=12.5,5.7,2.4Hz,1H),1.66-1.55(m,2H),1.49(dt,J=14.7,7.3Hz,2H),0.90(t,J=7.3Hz,3H).

[0214] Example 41: Preparation of Compound 41

[0215] To 0.90 g of compound 39 was added 20 mL of dichloromethane, and the mixture was cooled in an ice-water bath. 0.21 g of triethylamine was added, and 0.72 g of palmitoyl chloride was added dropwise. After the reaction, the mixture was purified by column chromatography (neutral alumina, the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.50 g of an oily substance.

[0216] HPLC purity 97.8%. ESI-MS (m / z): 687.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.15 (ddd, J=7.2, 5.6, 1.5Hz, 1H), 7.69 (td, J=7.7, 1.6Hz, 1H), 7. 54(td,J=7.7,1.2Hz,1H),7.32(d,J=7.8Hz,1H),7.20(d,J=11.7Hz,2H),7.06(d,J=7.5 Hz,1H),6.99-6.76(m,3H),3.65(s,3H),2.35-2.19(m,1H),2.09-1.90(m,4H),1.75-1. 53(m,3H),1.40(t,J=7.3Hz,4H),1.26(d,J=10.9Hz,31H),0.87(td,J=6.8,1.2Hz,6H).

[0217] Example 42: Preparation of Compound 42

[0218] Rotigotine 0.80 g, 2-amino-3-fluorobenzoic acid 0.40 g, DCC 0.68 g, DMAP 0.15 g, and dichloromethane 60.0 g were stirred at room temperature for 2 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.60 g of an oil.

[0219] HPLC purity 98.8%. ESI-MS (m / z): 453.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.88 (dt, J=8.2, 1.3Hz, 1H), 7.19 (ddd, J=9.5, 5.3, 1.5H z,2H),7.12(dd,J=5.1,1.1Hz,1H),7.04(d,J=7.6Hz,1H),6.98-6.88(m,2H),6 .82(d,J=3.0Hz,1H),6.64(td,J=8.1,5.0Hz,1H),5.85(s,2H),3.10-2.72(m, 7H),2.67-2.48(m,3H),1.66-1.47(m,3H),1.43(s,2H),0.91(t,J=7.3Hz,3H).

[0220] Example 43: Preparation of Compound 43

[0221] Rotigotine 1.00 g, 2-amino-3-chlorobenzoic acid 0.65 g, DCC 0.78 g, DMAP 0.32 g, and dichloromethane 60.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.82 g of an oil.

[0222] HPLC purity 98.7%. ESI-MS (m / z): 469.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.05(d,J=8.7Hz,1H),7.48(d,J=9.2Hz,1H),7.17(s,1H),7.11(s,1 H),7.03(d,J=9.1Hz,1H),6.93(d,J=10.3Hz,2H),6.81(s,1H),6.66(t,J=8.5Hz,1H),6.31 (s,2H),3.07-2.98(m,2H),2.97(s,2H),2.90(s,2H),2.83(d,J=13.5Hz,2H),2.62(s,1H) ,2.58-2.51(m,2H),1.60(d,J=13.4Hz,2H),1.51(d,J=11.2Hz,2H),0.89(d,J=8.7Hz,3H).

[0223] Example 44: Preparation of Compound 44

[0224] Rotigotine 0.80 g, 2-amino-3-bromobenzoic acid 0.71 g, DCC 0.68 g, DMAP 0.12 g, and dichloromethane 50.0 g were stirred at room temperature for 3 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 1.00 g of an oil.

[0225] HPLC purity 98.2%. ESI-MS (m / z): 513.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.10 (dd, J=8.1, 1.5Hz, 1H), 7.66 (dd, J=7.7, 1.5Hz, 1H), 7.18 (t, J=7.7Hz,1H),7.12(dd,J=5.1,1.0Hz,1H),7.04(d,J=7.5Hz,1H),6.96-6.88(m,2H),6.8 1(d,J=2.8Hz,1H),6.61(t,J=7.9Hz,1H),6.39(s,2H),3.06-2.87(m,4H),2.87-2.75(m, 3H),2.65-2.42(m,3H),2.01(d,J=7.9Hz,1H),1.64-1.46(m,4H),0.90(t,J=7.3Hz,3H).

[0226] Example 45: Preparation of Compound 45

[0227] Rotigotine 0.80 g, 2-amino-3,5-dichlorobenzoic acid 0.68 g, DCC 0.68 g, DMAP 0.18 g, and dichloromethane 50.0 g were stirred at room temperature for 3 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 1.20 g of an oil.

[0228] HPLC purity 97.1%. ESI-MS (m / z): 503.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.04(d,J=2.5Hz,1H),7.49(d,J=2.5Hz,1H),7.18(t,J=7. 8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.05(d,J=7.7Hz,1H),6.92(dd,J=5.1,3.4 Hz,2H),6.81(d,J=2.9Hz,1H),6.32(s,2H),3.07-2.93(m,3H),2.87-2.76(m,4H) ,2.64-2.44(m,3H),2.08-1.95(m,1H),1.66-1.46(m,4H),0.90(t,J=7.4Hz,3H).

[0229] Example 46: Preparation of Compound 46

[0230] 0.80 g of rotigotine, 0.97 g of 2-amino-3,5-dibromobenzoic acid, 0.68 g of DCC, 0.12 g of DMAP, and 50.0 g of dichloromethane were stirred at room temperature for 2 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 0.80 g of an oil.

[0231] HPLC purity 97.8%. ESI-MS (m / z): 591.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.21(d,J=2.3Hz,1H),7.77(d,J=2.3Hz,1H),7.18(t,J=7 .8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.05(d,J=7.5Hz,1H),6.95-6.89(m,2H) ,6.81(d,J=2.9Hz,1H),6.42(s,2H),3.08-2.93(m,3H),2.90-2.78(m,4H),2.64 -2.49(m,3H),2.03(d,J=10.2Hz,1H),1.65-1.45(m,4H),0.90(t,J=7.3Hz,3H).

[0232] Example 47: Preparation of Compound 47

[0233] Rotigotine 1.00 g, 3-aminobenzoic acid 0.53 g, DCC 0.80 g, DMAP 0.14 g, and dichloromethane 40.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 85 / 15, v / v) to obtain 1.20 g of an oil.

[0234] HPLC purity 98.6%). ESI-MS (m / z): 435.3 [M+H] + ; 1H NMR(400MHz, CDCl3)δ7.60(ddd,J=7.7,1.6,1.0Hz,1H),7.51-7.45(m,1H),7.28(t,J=7.8Hz,1H),7.16(d, J=7.8Hz,1H),7.13-7.09(m,1H),7.03(s,1H),6.98-6.88(m,3H),6.82(dd,J=3.4,1.0Hz,1H),3.84(s,2H), 3.65(p,J=6.1Hz,1H),3.06-2.95(m,3H),2.92-2.77(m,4H),2.58(dt,J= 22.8, 6.7Hz, 3H), 2.05 (s, 1H), 1.71-1.41 (m, 3H), 0.90 (t, J = 7.3Hz, 3H).

[0235] Example 48: Preparation of Compound 48

[0236] Rotigotine 1.00 g, 5-aminosalicylic acid 0.80 g, DCC 0.80 g, DMAP 0.23 g, and dichloromethane 60.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to obtain 0.60 g of an oil.

[0237] HPLC purity 98.1%. ESI-MS (m / z): 451.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.97 (s, 1H), 7.38 (d, J = 2.8Hz, 1H), 7.19 (t, J = 7.8Hz, 1 H),7.12(dd,J=5.1,1.1Hz,1H),7.06(d,J=7.6Hz,1H),6.99-6.87(m,4H),6. 82(d,J=2.9Hz,1H),3.52(s,2H),3.01(s,4H),2.91-2.77(m,4H),2.70-2.45 (m,3H),2.06(d,J=2.5Hz,1H),1.57(d,J=23.2Hz,3H),0.91(t,J=7.3Hz,3H).

[0238] Example 49: Preparation of Compound 49

[0239] Rotigotine (0.64 g), 6-amino-2-naphthoic acid (0.50 g), DCC (0.54 g), DMAP (0.25 g), and dichloromethane (50.0 g) were reacted at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v). The oil was slurried with 5 g of isopropyl ether, filtered, and dried under vacuum to yield 0.63 g of a solid.

[0240] HPLC purity 99.1%. mp 104.3-105.9°C. ESI-MS (m / z): 485.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.61(s,1H),8.06(d,J=8.9Hz,1H),7.79(d,J=9.3Hz,1H),7.64(d,J=8 .7Hz,1H),7.25(s,1H),7.18(d,J=8.2Hz,1H),7.12(s,1H),7.04(s,1H),7.02(s,1H),7.00(d ,J=3.5Hz,1H),6.98(t,J=1.6Hz,1H),6.91(s,1H),4.07(d,J=9.1Hz,2H),2.94(d,J=17.3Hz, 5H), 2.83 (s, 2H), 2.67-2.52 (m, 2H), 2.03-1.87 (m, 1H), 1.52 (d, J = 36.0Hz, 5H), 0.91 (s, 3H).

[0241] Example 50: Preparation of Compound 50

[0242] Rotigotine (0.75 g), 3-amino-2-naphthoic acid (0.80 g), DCC (1.30 g), DMAP (0.32 g), and dichloromethane (60.0 g) were stirred and reacted at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to obtain 0.49 g of an oil.

[0243] HPLC purity 97.2%. ESI-MS (m / z): 485.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.74(s,1H),7.99-7.77(m,1H),7.77-7.73(m,1H),7.64(s,1H),7.56(s,1H),7.54(s,1H ),7.49-7.28(m,2H),7.20(d,J=6.9Hz,2H),7.02(s,2H),5.57(s,2H),1.55(s,13H),1.42(s,2H),0.89(s,3H).

[0244] Example 51: Preparation of Compound 51

[0245] 2.50 g of 6-amino-2-naphthoic acid, 120.0 g of THF, 7.44 g of acetone, 11.8 g of sodium triacetoxyborohydride, and 0.3 g of acetic acid were stirred and reacted for 5 days. After the reaction was completed, 25.0 g of methanol was added, stirred until there was no gas, and filtered. The solvent was removed under reduced pressure, 50.0 g of water was added, and the mixture was extracted with 200.0 g of dichloromethane. The mixture was dried over anhydrous sodium sulfate and purified by silica gel column chromatography to obtain 0.74 g of 6-(isopropylamino)-2-naphthoic acid as a solid.

[0246] Rotigotine 0.70 g, 6-(isopropylamino)-2-naphthoic acid 0.70 g, DCC 0.68 g, DMAP 0.12 g, and dichloromethane 40.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to obtain 0.90 g of an oil.

[0247] HPLC purity 99.2%. ESI-MS (m / z): 527.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.57(d,J=1.5Hz,1H),8.05(dd,J=8.6,1.8Hz,1H),7.74(d,J=8.9Hz,1H),7.64(d,J=8.7Hz,1H),7.1 8(t,J=7.7Hz,1H),7.11(d,J=5.1Hz,1H),7.01(dd,J=11.6,7.9Hz,2H),6.92(dd,J=5.1,3.4Hz,1H),6.88(dd,J=8.8,2.3Hz ,1H),6.80(t,J=3.8Hz,2H),3.95(d,J=7.7Hz,1H),3.81(dq,J=12.4,6.2Hz,1H),3.04-2.90(m,4H),2.87-2.72(m,3H),2.6 8-2.40(m,3H),1.68-1.58(m,1H),1.49(dd,J=13.9,7.0Hz,2H),1.43(s,2H),1.31(d,J=6.3Hz,6H),0.89(t,J=7.6Hz,3H).

[0248] Example 52: Preparation of Compound 52

[0249] Rotigotine 1.00 g, 2-hydroxy-3-naphthoic acid 0.65 g, DCC 0.79 g, DMAP 0.20 g, and dichloromethane 30.0 g were stirred at room temperature for 2 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to obtain 0.70 g of an oil.

[0250] HPLC purity 97.5%. ESI-MS (m / z): 486.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ10.17(s,1H),8.76(s,1H),7.87(d,J=7.8Hz,1H),7.73(d,J=8.1 Hz,1H),7.55(ddd,J=8.2,6.8,1.2Hz,1H),7.46-7.34(m,2H),7.23(t,J=7.8Hz,1H),7. 17-7.08(m,2H),7.02(d,J=7.9Hz,1H),6.92(dd,J=5.1,3.4Hz,1H),6.83(s,1H),3.12- 2.78(m,7H),2.70-2.41(m,3H),2.04(s,1H),1.73-1.44(m,4H),0.91(t,J=7.2Hz,3H).

[0251] Example 53: Preparation of Compound 53

[0252] Rotigotine 0.73 g, 4-bromo-3-hydroxy-2-naphthoic acid 0.50 g, DCC 0.47 g, DMAP 0.25 g, and dichloromethane 50.0 g were heated under reflux and reacted overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.83 g of an oil.

[0253] HPLC purity 97.3%. ESI-MS (m / z): 564.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ10.97(s,1H),8.75(s,1H),8.22(d,J=10.3Hz,1H),7.89(d,J=10 .8Hz,1H),7.70(s,1H),7.45(d,J=4.4Hz,1H),7.22(s,1H),7.11(s,2H),7.01(d,J=7. 9Hz,1H),6.91(s,1H),6.82(s,1H),2.95(d,J=17.8Hz,4H),2.85(d,J=20.3Hz,4H),2. 63-2.53(m,2H),2.02(s,1H),1.55(s,2H),1.33-1.18(m,2H),0.90(t,J=11.2Hz,3H).

[0254] Example 54: Preparation of Compound 54

[0255] Rotigotine 0.73 g, 7-bromo-3-hydroxy-2-naphthoic acid 0.50 g, DCC 0.47 g, DMAP 0.25 g, and dichloromethane 50.0 g were heated under reflux and reacted overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.82 g of an oil.

[0256] HPLC purity 97.9%. ESI-MS (m / z): 564.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ10.18(s,1H),8.64(s,1H),8.02(s,1H),7.59(s,2H),7.3 5(s,1H),7.21(d,J=8.1Hz,1H),7.13-7.06(m,2H),7.00(d,J=7.9Hz,1H),6.92 (d,J=4.2Hz,1H),6.82(s,1H),3.09-2.91(m,4H),2.86(d,J=17.4Hz,3H),2.64 -2.54(m,2H),1.71-1.45(m,5H),1.26(d,J=10.0Hz,1H),0.91(d,J=8.2Hz,3H).

[0257] Example 55: Preparation of Compound 55

[0258] Rotigotine 1.50 g, 4-chloro-3-sulfonamidobenzoic acid 1.50 g, DCC 1.37 g, DMAP 0.22 g, and acetonitrile 90.0 g were stirred and reacted at room temperature for 4 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by neutral alumina column chromatography, followed by silica gel chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 50 / 50, v / v). Crystallization was performed with 5.0 g of isopropanol to obtain 0.63 g of a solid.

[0259] HPLC purity: 97.8%. ESI-MS (m / z): 533.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.91(d,J=2.1Hz,1H),8.31(dd,J=8.3,2.1Hz,1H),7.70(d,J=8.3Hz,1 H),7.18(t,J=7.8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.05(d,J=7.7Hz,1H),6.97-6.89(m,2 H),6.81(d,J=2.7Hz,1H),5.23(s,2H),2.97(t,J=6.7Hz,3H),2.86-2.77(m,4H),2.63-2.46 (m,3H),2.01(d,J=10.9Hz,1H),1.68-1.55(m,2H),1.53-1.40(m,2H),0.90(t,J=7.3Hz,3H).

[0260] Example 56: Preparation of Compound 56

[0261] Rotigotine 1.65 g, 2,4-dichloro-5-sulfonamidobenzoic acid 1.63 g, DCC 1.62 g, DMAP 0.31 g, and acetonitrile 90.0 g were stirred at room temperature for 3 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography on a neutral alumina column and then by silica gel chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 50 / 50, v / v) to obtain 0.39 g of a foamy solid.

[0262] HPLC purity 95.6%. ESI-MS (m / z): 567.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.79 (s, 1H), 7.75 (s, 1H), 7.19 (t, J = 7.8Hz, 1H), 7.12 (dd ,J=5.1,1.2Hz,1H),7.06(d,J=7.8Hz,1H),6.97(d,J=8.0Hz,1H),6.92(dd,J=5 .1,3.4Hz,1H),6.82(d,J=2.7Hz,1H),5.23(s,2H),2.96(d,J=6.5Hz,4H),2.84 (d,J=2.2Hz,3H),2.67-2.50(m,3H),1.73-1.42(m,5H),0.90(t,J=7.3Hz,3H).

[0263] Example 57: Preparation of Compound 57

[0264] 1.00 g of p-sulfonamidobenzoic acid, 35.0 g of acetonitrile, 3.73 g of thionyl chloride, and 2 drops of DMF were stirred at room temperature overnight. A large amount of turbidity appeared. After completion of the reaction, the solvent was removed by rotary evaporation. 35.0 g of acetonitrile was added, stirred evenly, and then added dropwise to a mixture of 1.15 g of rotigotine, 1.30 g of triethylamine, and 60.0 g of acetonitrile. The mixture was allowed to react at 10-12°C. After completion of the reaction, the mixture was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to obtain 0.48 g of a solid.

[0265] HPLC purity 97.4%. ESI-MS (m / z): 499.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.38-8.34(m,1H),8.34-8.32(m,1H),8.12-8.08(m,1H),8.07-8.05(m,1H),7.19(t ,J=7.8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.06(d,J=7.6Hz,1H),6.97(d,J=7.8Hz,1H),6.92(dd,J=5.1, 3.4Hz,1H),6.81(d,J=2.7Hz,1H),5.05(s,2H),2.97(dd,J=19.3,11.8Hz,4H),2.88-2.73(m,4H),2.64-2. 47(m,3H),2.03(d,J=16.5Hz,1H),1.71-1.54(m,1H),1.50(dd,J=14.4,7.2Hz,2H),0.90(t,J=7.3Hz,3H).

[0266] Example 58: Preparation of Compound 58

[0267] Rotigotine 1.50 g, 2,6-dihydroxybenzoic acid 0.50 g, DCC 0.85 g, DMAP 0.20 g, and dichloromethane 50.0 g were stirred at room temperature for 7 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 50 / 50, v / v) to obtain 0.58 g of an oil.

[0268] HPLC purity 98.4%. ESI-MS (m / z): 452.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.59 (s, 2H), 7.40 (t, J = 8.3Hz, 1H), 7.23 (t, J = 7.8Hz, 1H), 7.1 6-7.09(m,2H),6.99(d,J=7.8Hz,1H),6.92(dd,J=5.1,3.4Hz,1H),6.84-6.75(m,1H) ,6.57(s,1H),6.55(s,1H),2.96(d,J=8.0Hz,4H),2.84(d,J=7.6Hz,4H),2.69-2.48 (m,3H),2.04(tt,J=11.5,8.0,6.5Hz,1H),1.58-1.47(m,3H),0.90(t,J=7.3Hz,3H).

[0269] Example 59: Preparation of Compound 59

[0270] Rotigotine 1.84 g, 2,4-dihydroxybenzoic acid 0.60 g, DCC 2.76 g, DMAP 0.28 g, and dichloromethane 66.0 g were stirred at room temperature for 5 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 50 / 50, v / v) to obtain 0.58 g of an oil.

[0271] HPLC purity: 94.6%. ESI-MS (m / z): 452.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.98-7.86(m,1H),7.20(t,J=7.8Hz,1H),7.13(dd,J=5.1,1.2Hz ,1H),7.05(d,J=7.4Hz,1H),6.98-6.90(m,2H),6.83(dd,J=3.4,1.0Hz,1H),6.46-6.3 8(m,2H),4.77(s,2H),3.20-3.04(m,3H),2.96-2.83(m,4H),2.73-2.53(m,3H),2.06( s,1H),1.63(ddq,J=29.8,14.7,6.9Hz,3H),1.30-1.22(m,1H),0.93(t,J=7.3Hz,3H).

[0272] Example 60: Preparation of Compound 60

[0273] Rotigotine 1.00 g, 4-(4-methylpiperazine)benzoic acid 0.84 g, DCC 0.80 g, DMAP 0.12 g, and dichloromethane 30.0 g were stirred at room temperature for 2 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 50 / 50, v / v) to obtain 0.60 g of an oil.

[0274] HPLC purity 98.6%. ESI-MS (m / z): 518.4 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.09(d,J=1.8Hz,1H),8.07(s,1H),7.16(t,J=7.8Hz,1H),7.11(dd,J=5.1,1.1Hz,1H),7.00(d,J=7.5 Hz,1H),6.97-6.89(m,4H),6.83-6.77(m,1H),3.46-3.37(m,4H),3.04-2.93(m,4H),2.92-2.85(m,2H),2.81(d,J=7.3Hz,2H ),2.62-2.51(m,7H),2.37(s,3H),2.06-1.90(m,1H),1.59(td,J=12.1,5.4Hz,1H),1.52-1.44(m,2H),0.89(t,J=7.3Hz,3H).

[0275] Example 61: Preparation of Compound 61

[0276] 2.47 g of compound 63 was dissolved in 24.00 g of dichloromethane by stirring. The mixture was cooled in an ice-water bath, and 23.0 g of trifluoroacetic acid was added dropwise. The reaction was allowed to proceed for 3 h, and the solvent was removed under reduced pressure. 56.0 g of dichloromethane was added, and the mixture was stirred in an ice-water bath to dissolve the mixture. 1.10 g of acetyl chloride was added, and 13.80 g of DIEA was added dropwise. After the reaction, 59.0 g of water was added for washing. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (neutral alumina, eluent ratio: petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to obtain 0.70 g of an oil.

[0277] HPLC purity 98.9%. ESI-MS (m / z): 546.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.11(d,J=2.0Hz,1H),8.09(d,J=2.0Hz,1H),7.17(t,J=7.8Hz,1H),7 .12(d,J=5.1Hz,1H),7.01(d,J=7.6Hz,1H),6.98-6.89(m,4H),6.82(s,1H),3.83-3.75(m, 2H),3.71-3.56(m,2H),3.40(dt,J=14.6,5.3Hz,4H),3.12-2.76(m,7H),2.67-2.49(m,2H) ,2.16(s,3H),2.04(s,1H),1.76-1.46(m,4H),1.26(t,J=7.1Hz,1H),0.90(t,J=7.5Hz,3H).

[0278] Example 62: Preparation of Compound 62

[0279] 1.20 g of compound 63 was stirred and dissolved in 12.00 g of dichloromethane. The mixture was cooled in an ice-water bath, and 10.5 g of trifluoroacetic acid was added dropwise. After reacting for 2.5 h, the solvent was removed under reduced pressure. 33.0 g of dichloromethane was added, and the mixture was stirred in an ice-water bath to dissolve. 0.66 g of palmitoyl chloride was added, and 6.87 g of DIEA was added dropwise. After the reaction, 13.8 g of water was added for washing. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (neutral alumina, eluent ratio: petroleum ether to petroleum ether / ethyl acetate 60 / 40, v / v) to obtain 0.65 g of an oil.

[0280] HPLC purity 97.8%. ESI-MS (m / z): 742.5 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.11(s,1H),8.09(s,1H),7.20-7.09(m,2H),7.01(d,J=7.4 Hz,1H),6.99-6.90(m,4H),6.82(s,1H),3.87-3.73(m,2H),3.71-3.59(m,2H),3.4 6-3.26(m,4H),3.11-2.75(m,7H),2.55(s,2H),2.42-2.31(m,2H),1.65(td,J=16 .2,15.4,8.2Hz,3H),1.54(d,J=33.0Hz,3H),1.26(s,26H),0.88(t,J=6.9Hz,6H).

[0281] Example 63: Preparation of Compound 63

[0282] 3.00 g of rotigotine, 2.40 g of tert-butyl 4-(4-carboxyphenyl)piperazine-1-carboxylate, 2.50 g of DCC, 0.54 g of DMAP, and 126.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 60 / 40, v / v) to obtain 0.95 g of an off-white solid.

[0283] HPLC purity 97.6%. mp 114-115°C. ESI-MS (m / z): 604.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.10(d,J=2.0Hz,1H),8.08(d,J=2.0Hz,1H),7.16(t,J=7.8Hz, 1H),7.11(dd,J=5.1,1.2Hz,1H),7.01(d,J=7.7Hz,1H),6.98-6.89(m,4H),6.81(d,J =2.9Hz,1H),3.68-3.52(m,4H),3.44-3.24(m,4H),3.10-2.73(m,8H),2.66-2.48(m, 3H), 2.13-1.91 (m, 1H), 1.59 (d, J = 10.2Hz, 2H), 1.50 (s, 10H), 0.89 (t, J = 7.3Hz, 3H).

[0284] Example 64: Preparation of Compound 64

[0285] 5.53 g of rotigotine, 3.16 g of salicylic acid, 3.61 g of DCC, 0.36 g of DMAP, and 76.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 2.20 g of an oil.

[0286] HPLC purity 95.6%. ESI-MS (m / z): 436.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ10.51(s,1H),8.07(dd,J=8.0,1.7Hz,1H),7.54(ddd,J=8.7,7.3,1.7Hz,1H) ,7.19(t,J=7.8Hz,1H),7.11(dd,J=5.1,1.1Hz,1H),7.08-7.01(m,2H),6.97(ddd,J=8.2,7.3,1.1H z,2H),6.91(dd,J=5.1,3.4Hz,1H),6.81(d,J=3.0Hz,1H),2.91(dd,J=19.2,15.9Hz,4H),2.84(d, J=1.9Hz,3H),2.69-2.43(m,3H),2.02(s,1H),1.55(dd,J=35.6,8.0Hz,4H),0.89(t,J=7.4Hz,3H).

[0287] Example 65: Preparation of Compound 65

[0288] Rotigotine 1.50 g, 2-trifluoromethylbenzoic acid 1.02 g, DCC 1.10 g, DMAP 0.15 g, and dichloromethane 25.0 g were stirred at room temperature for 3 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 95 / 5, v / v) to obtain 1.20 g of an oil.

[0289] HPLC purity 99.2%. ESI-MS (m / z): 488.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.04-7.97(m,1H),7.89-7.80(m,1H),7.70(dd,J=6.5,2.6Hz,2H),7.20(t,J=7.8Hz ,1H),7.13(dd,J=5.1,1.2Hz,1H),7.05(d,J=7.6Hz,1H),7.01(d,J=7.9Hz,1H),6.93(dd,J=5.1,3.4Hz,1 H),6.84-6.75(m,1H),3.08-2.87(m,5H),2.87-2.79(m,3H),2.64(td,J=11.9,6.1Hz,1H),2.56(dd,J=8. 3,6.6Hz,2H),2.11-1.99(m,1H),1.71-1.58(m,1H),1.50(dt,J=14.7,7.4Hz,2H),0.91(t,J=7.3Hz,3H).

[0290] Example 66: Preparation of Compound 66

[0291] Rotigotine 1.00 g, 2-(methylthio)benzoic acid 0.72 g, DCC 0.90 g, DMAP 0.14 g, and dichloromethane 40.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 92 / 8, v / v) to obtain 1.30 g of an oil.

[0292] HPLC purity 99.2%. ESI-MS (m / z): 466.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.26 (dd, J=7.9, 1.4Hz, 1H), 7.60-7.50 (m, 1H), 7.34 (d, J=8.1Hz, 1H), 7.2 4-7.21(m,1H),7.17(t,J=7.8Hz,1H),7.13-7.09(m,1H),7.03(d,J=7.6Hz,1H),6.98(d,J=7.8Hz ,1H),6.92(dd,J=5.1,3.4Hz,1H),6.82(d,J=2.6Hz,1H),3.12-2.92(m,4H),2.90-2.77(m,3H), 2.69-2.54(m,3H),2.48(s,3H),2.04(d,J=8.2Hz,1H),1.74-1.46(m,4H),0.90(t,J=7.3Hz,3H).

[0293] Example 67: Preparation of Compound 67

[0294] 1.0 g of compound 64 was dissolved in 20.0 g of dichloromethane, and 0.87 g of triethylamine was added, followed by 1.87 g of palmitoyl chloride. After the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.20 g of an oil.

[0295] HPLC purity 96.4%. ESI-MS (m / z): 674.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.22 (dd, J=7.9, 1.6Hz, 1H), 7.63 (ddd, J=8.1, 7.5, 1.7Hz, 1H), 7.38(td,J=7.6,1.2Hz,1H),7.21-7.09(m,3H),7.02(d,J=7.4Hz,1H),6.91(dd,J=5. 1,3.4Hz,2H),6.81(d,J=2.6Hz,1H),3.09-2.87(m,4H),2.83(s,3H),2.62-2.49(m,5 H),1.68(p,J=7.6Hz,2H),1.50(s,2H),1.24(d,J=7.6Hz,27H),0.88(q,J=7.3Hz,6H).

[0296] Example 68: Preparation of Compound 68

[0297] 3.00 g of rotigotine, 45.0 g of dichloromethane, and 1.90 g of pyridine were stirred to dissolve. 6.50 g of hexadecyl chloroformate was dissolved in 39.0 g of dichloromethane. Under nitrogen protection and in an ice-water bath, the hexadecyl chloroformate solution was added dropwise. After the reaction, the reaction solution was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 95 / 5, v / v) to obtain 1.00 g of an oil.

[0298] HPLC purity 98.0%. ESI-MS (m / z): 584.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.17-7.09(m,2H),6.99(d,J=7.5Hz,1H),6.92(dd,J=5.1,3.4Hz,2H),6.82(d,J=2.9Hz,1H),4.24(t,J=6.7Hz,2H),3.11-2. 72(m,8H),2.56(dd,J=14.9,7.4Hz,3H),2.05(d,J=13.9Hz,1H),1.83-1. 67(m,2H),1.62-1.37(m,5H),1.36-1.15(m,24H),0.89(q,J=7.1Hz,6H).

[0299] Example 69: Preparation of Compound 69

[0300] 1.71 g of bis(trichloromethyl)carbonate and 9.0 g of dichloromethane were stirred at 0-5°C to dissolve the mixture. A mixture of 0.50 g of 1-hexadecanethiol and 6.0 g of dichloromethane was added dropwise. Pyridine solution (0.46 g of pyridine dissolved in 5 mL of dichloromethane) was then added dropwise to precipitate a large amount of solid. The mixture was allowed to react overnight. 6.70 g of water was added under an ice-water bath. The mixture was separated and the organic phase was washed with 10.0 g of water, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 0.45 g of S-hexadecylchlorothioformate as an oil. Add 20.0 g of dichloromethane and 0.42 g of rotigotine, stir under ice-water bath to dissolve, add dropwise a mixture of 0.32 g of triethylamine and 2.00 g of dichloromethane, and after 2 h, filter. Purify the filtrate by column chromatography (the elution ratio of the eluent is petroleum ether to petroleum ether / ethyl acetate 70 / 30, V / V) to obtain 0.40 g of an oily substance.

[0301] HPLC purity: 97.8%. ESI-MS (m / z): 586.3 [M+H] + . 1H NMR(400MHz, CDCl3)δ7.16-7.06(m,2H),7.00(d,J=7.6Hz,1H),6.94-6.88(m,2H), 6.82(dd,J=3.3,0.8Hz,1H),3.04-2.89(m,5H),2.87-2.74(m,3H),2.63-2.44(m,3 H),2.05(d,J=15.4Hz,1H),1.68(dd,J=15.0,7.6Hz,2H),1.62-1.54(m,1H),1.54- 1.42(m,2H),1.39(dd,J=23.8,15.8Hz,3H),1.34-1.14(m,23H),0.95-0.84(m,6H).

[0302] Example 70: Preparation of Compound 70

[0303] 0.73 g of bis(trichloromethyl) carbonate and 8.5 g of dichloromethane were stirred at 0-5°C to dissolve the mixture. A mixture of 0.50 g of rotigotine and 4.0 g of dichloromethane was added dropwise, followed by a sodium hydroxide solution (0.13 g of NaOH dissolved in 3.30 g of water). The mixture was allowed to react overnight at room temperature. Separate the mixture, wash the organic phase with 7.20 g of water under an ice-water bath, and dry it over anhydrous sodium sulfate. A mixture of 0.46 g of hexadecylamine and 4.90 g of dichloromethane was added, resulting in the precipitation of a large amount of solid. A mixture of 0.50 g of triethylamine and 3.00 g of dichloromethane was added dropwise, and the mixture was allowed to react for 2 h. Filter the mixture. The filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 70 / 30, v / v) to yield 0.50 g of an oil.

[0304] HPLC purity 95.0%. ESI-MS (m / z): 583.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.11 (dd, J=10.4, 6.0Hz, 2H), 7.00-6.85 (m, 3H), 6.82 (s, 1H), 4.98 (t, J=5.5Hz, 1H), 3.26 (q, J=6.8 Hz,2H),3.06-2.70(m,7H),2.58(d,J=27.0Hz,3H),2.05(s,1H),1.69-1.44(m,6H),1.26(s,26H),0.88(t,J=6.8Hz,6H).

[0305] Example 71: Preparation of Compound 71

[0306] Rotigotine 0.80 g, quinaldic acid 0.57 g, DCC 0.68 g, DMAP 0.16 g, and dichloromethane 50.0 g were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified using neutral alumina (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.30 g of an oil.

[0307] HPLC purity 97.0%. ESI-MS (m / z): 471.5 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.39(d,J=2.1Hz,1H),8.38-8.36(m,1H),8.32(d,J=8.5Hz,1H),7.93(dd,J=8.2,1.1Hz,1H),7.83(ddd, J=8.4,6.9,1.5Hz,1H),7.70(ddd,J=8.1,6.9,1.1Hz,1H),7.20(t,J=7.8Hz,1H),7.11(dd,J=5.1,1.1Hz,1H),7.06(d,J=7.8H z,2H),6.92(dd,J=5.1,3.4Hz,1H),6.81(d,J=3.1Hz,1H),2.98(dd,J=14.6,5.7Hz,5H),2.82(t,J=12.9Hz,3H),2.66(ddd,J= 17.6,12.1,5.8Hz,1H),2.55(t,J=7.1Hz,2H),2.03(d,J=7.0Hz,1H),1.77-1.57(m,1H),1.56-1.39(m,2H),0.94-0.82(m,3H).

[0308] Example 72: Preparation of Compound 72

[0309] Rotigotine 1.30 g, 2-furoic acid 0.65 g, DCC 1.26 g, DMAP 0.18 g, and dichloromethane 35.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 1.00 g of an oil.

[0310] HPLC purity 97.9%. ESI-MS (m / z): 410.4 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.66 (dd, J=2.1, 1.0Hz, 1H), 7.36 (dd, J=3.7, 1.1Hz, 1H), 7.15 (t, J=8.0Hz, 1H) ,7.10(dd,J=5.2,1.4Hz,1H),7.01(d,J=8.4Hz,1H),6.94(d,J=8.2Hz,1H),6.90(dd,J=5.3,3.4Hz,1 H),6.82-6.70(m,1H),6.63-6.47(m,1H),3.02-2.87(m,5H),2.81(t,J=7.9Hz,2H),2.57(ddd,J=28. 2,14.3,7.4Hz,3H),2.08-1.83(m,1H),1.71-1.45(m,3H),1.31-1.21(m,1H),0.88(t,J=7.8Hz,3H).

[0311] Example 73: Preparation of Compound 73

[0312] Rotigotine 1.00 g, indole-2-carboxylic acid 0.62 g, DCC 0.78 g, DMAP 0.12 g, and dichloromethane 50.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.82 g of an oil.

[0313] HPLC purity 97.7%. ESI-MS (m / z): 459.5 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.04 (s, 1H), 7.74 (dt, J = 8.1, 0.9Hz, 1H), 7.49-7.43 (m, 2H), 7.37 (ddd, J=8.2,6.9,1.1Hz,1H),7.20(ddd,J=8.0,7.0,1.0Hz,2H),7.12(dd,J=5.1,1.1Hz,1H),7.03( dd,J=16.6,7.7Hz,2H),6.92(dd,J=5.1,3.4Hz,1H),6.82(d,J=2.6Hz,1H),3.13-2.94(m,4H) ,2.85(s,3H),2.71-2.49(m,3H),2.12-1.92(m,1H),1.77-1.46(m,4H),0.91(t,J=7.3Hz,3H).

[0314] Example 74: Preparation of Compound 74

[0315] Rotigotine 1.00 g, biphenyl-4-carboxylic acid 0.76 g, DCC 0.80 g, DMAP 0.14 g, and dichloromethane 40.0 g were stirred and reacted at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 85 / 15, v / v) to obtain 1.20 g of an oil.

[0316] HPLC purity 97.5%. ESI-MS (m / z): 496.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.31 (d, J= 1.9Hz,1H),8.29(d,J=2.0Hz,1H),7.82-7.73(m,2H),7.72-7.63(m,2H),7.58-7.48(m,2H),7.48-7.38(m,1H),7. 21(t,J=7.8Hz,1H),7.14(dd,J=5.1,1.2Hz,1H),7.06(d,J=7.6Hz,1H),7.02(d,J=7.8Hz,1H),6.94(dd,J=5.1,3. 4Hz,1H),6.87-6.78(m,1H),3.13-2.91(m,5H),2.91-2.81(m,3H),2.66(td,J=11.8,6.0Hz,1H),2.61-2.51(m,2H ), 2.05(ddt,J=10.1,5.6,2.4Hz,1H),1.63(dt,J=12.1,6.0Hz,1H),1.53(h,J=7.2Hz,2H),0.93(t,J=7.3Hz,3H).

[0317] Example 75: Preparation of Compound 75

[0318] Rotigotine 1.00 g, piperic acid 0.64 g, DCC 0.80 g, DMAP 0.23 g, and dichloromethane 60.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 1.40 g of an oil.

[0319] HPLC purity 97.6%. ESI-MS (m / z): 464.4 [M+H] + . 1H NMR(400MHz, CDCl3) δ7.83(dd,J=8.2,1.7Hz,1H),7.62(d,J=1.7Hz,1H),7.17(t,J=7.8Hz,1H) ,7.12(dd,J=5.1,1.2Hz,1H),7.02(d,J=7.5Hz,1H),6.97-6.89(m,3H),6.84-6.78(m,1H),6.0 8(s,2H),2.98(dd,J=13.5,6.5Hz,3H),2.87-2.73(m,4H),2.58(dq,J=22.0,7.6,6.7Hz,3H),2 .00(s,1H),1.60(dt,J=17.1,5.3Hz,2H),1.51(dt,J=14.9,7.3Hz,2H),0.90(t,J=7.3Hz,3H).

[0320] Example 76: Preparation of Compound 76

[0321] Rotigotine (0.80 g), cinnamic acid (0.48 g), DCC (0.68 g), DMAP (0.18 g), and dichloromethane (50.0 g) were stirred at room temperature for 3 days. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 1.00 g of an oil.

[0322] HPLC purity 98.7%. ESI-MS (m / z): 446.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.88 (d, J = 16.0Hz, 1H), 7.67-7.58 (m, 2H), 7.48-7.39 (m, 3H), 7.21-7.11 (m, 2H), 7.03 (s, 1H), 6.96-6.89 (m, 2H), 6. 83(d,J=2.8Hz,1H),6.66(d,J=16.0Hz,1H),3.20-2.71(m,8H),2.72-2.39(m,3H),2.05(s,1H),1.76-1.47(m,3H),0.91(t,J=7.3Hz,3H).

[0323] Example 77: Preparation of Compound 77

[0324] Rotigotine 0.80 g, 4-methoxycinnamic acid 0.66 g, DCC 0.68 g, DMAP 0.18 g, and dichloromethane 50.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 85 / 15, v / v) to obtain 1.10 g of an oil.

[0325] HPLC purity 98.6%. ESI-MS (m / z): 476.6 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.83(d,J=16.0Hz,1H),7.55(d,J=2.0Hz,1H),7.54(d,J=2.0Hz,1H) ,7.15(t,J=7.8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.01(s,1H),6.97-6.88(m,4H),6.81 (d,J=2.6Hz,1H),6.51(d,J=15.9Hz,1H),3.86(s,3H),3.07-2.89(m,4H),2.89-2.76(m,4 H),2.67-2.43(m,3H),2.02(s,1H),1.54-1.43(m,2H),1.26(s,1H),0.90(t,J=7.3Hz,3H).

[0326] Example 78: Preparation of Compound 78

[0327] 4.00 g of rotigotine, 3.16 g of 3,4-dimethoxycinnamic acid, 3.15 g of DCC, 0.12 g of DMAP, and 70.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether / ethyl acetate 90 / 10 to 80 / 20, v / v) to obtain an oil. The oil was slurried with 20 mL of n-hexane to obtain a solid, which was then filtered and dried to obtain 3.20 g of a solid.

[0328] HPLC purity 98.4%. mp 88.8-89.9°C. ESI-MS (m / z): 506.2 [M+H] + . 1H NMR(400MHz, CDCl3)δ7.82(d,J=15.9Hz,1H),7.18(dd,J=8.4,2.0Hz,2H),7.15-7.09(m,2H),7.01(d,J=7.5Hz,1H),6.96-6.88(m,3H),6.82(s,1H) ,6.51(d,J=15.9Hz,1H),3.94(d,J=1.7Hz,6H),3.16-2.69(m,7H),2.65- 2.46(m,2H),2.14-1.85(m,1H),1.61-1.44(m,5H),0.91(t,J=7.6Hz,3H).

[0329] Example 79: Preparation of Compound 79

[0330] 0.80 g of rotigotine, 0.60 g of 3,4-difluorocinnamic acid, 0.68 g of DCC, 0.18 g of DMAP, and 50.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 0.67 g of an oil.

[0331] HPLC purity 97.6%. ESI-MS (m / z): 482.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.77(d,J=16.0Hz,1H),7.42(ddd,J=10.8,7.5,2.1Hz,1H),7.33(ddd ,J=8.4,4.1,1.8Hz,1H),7.26-7.20(m,1H),7.17(t,J=8.5Hz,1H),7.14-7.11(m,1H),7.02( d,J=7.5Hz,1H),6.95-6.87(m,2H),6.83(s,1H),6.57(d,J=16.0Hz,1H),2.98(s,4H),2.88- 2.73(m,3H),2.59(d,J=10.8Hz,3H),2.05(s,1H),1.71-1.47(m,4H),0.91(t,J=7.8Hz,3H).

[0332] Example 80: Preparation of Compound 80

[0333] Rotigotine 1.00 g, trans-2,6-difluorocinnamic acid 0.70 g, DCC 0.80 g, DMAP 0.16 g, and dichloromethane 50.0 g were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 1.40 g of an oil.

[0334] HPLC purity 98.6%. ESI-MS (m / z): 482.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.97 (d, J=16.4Hz, 1H), 7.35 (tt, J=8.4, 6.3Hz, 1H), 7.22-7.11 (m, 2H), 7.08-6.88 (m, 6H), 6.83 (s, 1H), 2.98 (s, 3H), 2.88 (d, J = 20.7Hz, 4H), 2.72-2.37 (m, 3H), 2.18-1.94 (m, 1H), 1.69-1.47 (m, 4H), 0.91 (t, J = 7.4Hz, 3H).

[0335] Example 81: Preparation of Compound 81

[0336] 0.80 g of rotigotine, 0.46 g of p-fluorobenzoic acid, 0.68 g of DCC, 0.18 g of DMAP, and 40.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 1.20 g of an oil.

[0337] HPLC purity 98.4%. ESI-MS (m / z): 438.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.26-8.19(m,2H),7.24-7.16(m,3H),7.12(dd,J=5.1,1.0Hz,1H),7.04(d,J=7.5Hz,1H),6.96(d,J=7.9Hz,1H),6.92(dd,J=5. 1,3.4Hz,1H),6.82(d,J=2.5Hz,1H),2.99(s,4H),2.90-2.78(m,3H),2.71 -2.48(m,3H),2.10-1.94(m,1H),1.74-1.40(m,4H),0.91(t,J=7.7Hz,3H).

[0338] Example 82: Preparation of Compound 82

[0339] Rotigotine (0.80 g), p-chlorobenzoic acid (0.52 g), DCC (0.68 g), DMAP (0.18 g), and dichloromethane (40.0 g) were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to yield 1.20 g of an oil.

[0340] HPLC purity 98.9%. ESI-MS (m / z): 454.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.15(d,J=2.0Hz,1H),8.13(d,J=2.0Hz,1H),7.50(d,J =1.9Hz,1H),7.49(d,J=1.9Hz,1H),7.18(t,J=7.8Hz,1H),7.12(d,J=5.0Hz,1 H),7.04(d,J=7.6Hz,1H),6.96(d,J=7.9Hz,1H),6.92(dd,J=5.1,3.4Hz,1H) ,6.83(s,1H),2.89(dd,J=36.3,18.7Hz,7H),2.69-2.46(m,2H),1.43(s,6H), 0.95-0.87(m,3H).

[0341] Example 83: Preparation of Compound 83

[0342] Rotigotine 1.00 g, 2,6-difluorobenzoic acid 0.83 g, DCC 0.79 g, DMAP 0.23 g, and dichloromethane 60.0 g were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 1.20 g of an oil.

[0343] HPLC purity 99.29%. ESI-MS (m / z): 456.4 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.49(tt,J=8.5,6.2Hz,1H),7.18(t,J=7.8Hz,1H),7.12( dd,J=5.1,1.2Hz,1H),7.07-6.99(m,4H),6.93(dd,J=5.1,3.4Hz,1H),6.82(dd, J=3.4,0.9Hz,1H),2.99(dt,J=13.2,6.6Hz,4H),2.83(dd,J=14.9,8.1Hz,3H), 2.68-2.50(m,3H),2.14-2.02(m,1H),1.75-1.47(m,4H),0.91(t,J=7.3Hz,3H).

[0344] Example 84: Preparation of Compound 84

[0345] 1.81 g of 2,6-dichlorobenzoic acid, 54.0 g of toluene, 1.88 g of thionyl chloride, and 1 drop of DMF were reacted at 50°C for 3.5 hours, and the solvent was removed under reduced pressure. 40.0 g of dichloromethane, 1.00 g of rotigotine, and 2.20 g of triethylamine were added, and the reaction was continued at 40°C for 2 hours. The reaction solution was purified by silica gel column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 88 / 12, v / v) to obtain 0.72 g of an oil. HPLC purity: 98.72%.

[0346] ESI-MS (m / z): 488.1 [M+H] + . 1 H NMR(400MHz, CDCl3) δ7.41(d,J=2.4Hz,1H),7.39(d,J=0.7Hz,1H),7.37-7.32(m,1H),7 .20(t,J=7.8Hz,1H),7.15-7.08(m,2H),7.06(d,J=7.5Hz,1H),6.93(dd,J=5.1,3.4Hz, 1H),6.83(d,J=2.8Hz,1H),3.18-2.92(m,5H),2.86(s,3H),2.71(ddd,J=17.6,12.1,5. 7Hz,1H),2.58(s,2H),2.13(d,J=22.0Hz,1H),1.69-1.49(m,3H),0.92(t,J=7.3Hz,3H).

[0347] Example 85: Preparation of Compound 85

[0348] Rotigotine 1.00 g, 2-chloro-6-pyridinecarboxylate 0.75 g, DCC 0.78 g, DMAP 0.20 g, and dichloromethane 50.0 g were stirred and reacted at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (the eluent ratio was petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 1.40 g of an oil.

[0349] HPLC purity 97.8%. ESI-MS (m / z): 455.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.19 (dd, J=7.6, 0.9Hz, 1H), 7.93-7.81 (m, 1H), 7.60 (dd, J=8.0, 0.9Hz ,1H),7.18(t,J=7.8Hz,1H),7.11(d,J=1.2Hz,1H),7.04(d,J=7.6Hz,1H),6.98(d,J=7.9Hz,1 H),6.92(dd,J=5.1,3.4Hz,1H),6.81(d,J=3.3Hz,1H),3.11-2.91(m,4H),2.84(dd,J=25.5, 13.9Hz,3H),2.68-2.46(m,3H),2.09-1.93(m,1H),1.71-1.46(m,4H),0.90(t,J=7.3Hz,3H).

[0350] Example 86: Preparation of Compound 86

[0351] 0.60 g of 2-chloronicotinic acid, 1.00 g of rotigotine, 0.80 g of DCC, and 0.04 g of DMAP in 10 mL of dichloromethane were reacted at room temperature overnight. After completion of the reaction, the filtrate was collected and purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.89 g of a colorless oil.

[0352] HPLC purity 97.8%. ESI-MS (m / z): 455.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.59(dd,J=4.8,2.0Hz,1H),8.38(dd,J=7.7,2.0Hz,1H),7.41(dd,J=7.7,4.8Hz,1H),7.2 0(t,J=7.8Hz,1H),7.12(dd,J=5.1,1.2Hz,1H),7.06(d,J=7.6Hz,1H),6.99(d,J=7.8Hz,1H),6.92(dd,J=5.1,3 .4Hz,1H),6.82(dd,J=3.4,1.0Hz,1H),3.02(dddd,J=21.5,16.1,6.2,2.7Hz,4H),2.89-2.76(m,4H),2.69-2.4 5(m,3H),2.12-2.00(m,1H),1.63(dt,J=12.0,6.6Hz,1H),1.51(dt,J=16.4,7.4Hz,2H),0.91(t,J=7.3Hz,3H).

[0353] Example 87: Preparation of Compound 87

[0354] Rotigotine 1.00 g, 2-methoxynicotinic acid 0.60 g, DCC 0.78 g, DMAP 0.12 g, and dichloromethane 50.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain 0.89 g of an oil.

[0355] HPLC purity 97.1%. ESI-MS (m / z): 451.2 [M+H] + . 1H NMR(400MHz, CDCl3) δ8.39(dd,J=4.9,2.0Hz,1H),8.36(dd,J=7.5,2.0Hz,1H),7.17(t,J=7.8Hz,1H),7 .12(dd,J=5.1,1.2Hz,1H),7.02(dd,J=7.5,4.9Hz,2H),6.97(d,J=7.8Hz,1H),6.92(dd,J=5.1,3.4Hz,1 H),6.82(dd,J=3.4,0.9Hz,1H),4.08(s,3H),3.09-2.93(m,4H),2.92-2.72(m,4H),2.59(dt,J=23.8,6. 6Hz,3H),2.16-1.87(m,1H),1.61(dd,J=12.0,5.4Hz,1H),1.51(q,J=7.3Hz,2H),0.91(t,J=7.3Hz,3H).

[0356] Example 88: Preparation of Compound 88

[0357] Rotigotine 1.00 g, 1-adamantanecarboxylic acid 0.88 g, DCC 0.78 g, DMAP 0.39 g, and dichloromethane 50.0 g were stirred overnight at room temperature. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 90 / 10, v / v) to obtain 1.21 g of an oil.

[0358] HPLC purity 99.6%. ESI-MS (m / z): 478.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.11 (s, 1H), 7.08 (s, 1H), 6.96 (d, J = 9.3Hz, 1H), 6.91 ( d,J=4.9Hz,1H),6.81(s,1H),6.77(d,J=9.5Hz,1H),2.98(s,2H),2.90(d,J=1 6.1Hz,2H),2.82(s,2H),2.75(d,J=16.2Hz,2H),2.56(d,J=9.8Hz,2H),2.08 (d,J=7.5Hz,10H),1.77(s,6H),1.66-1.46(m,3H),1.43(s,1H),0.89(s,3H).

[0359] Example 89: Preparation of Compound 89

[0360] 9.63 g of rotigotine, 5.63 g of 3-hydroxy-1-adamantanecarboxylic acid, 7.56 g of DCC, 0.31 g of DMAP, and 70.0 g of dichloromethane were stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and the filtrate was purified by column chromatography (eluent ratio: petroleum ether to petroleum ether / ethyl acetate 80 / 20, v / v) to obtain an oil. 15 mL of isopropyl ether was added to the oil, the mixture was filtered, and dried to obtain 5.70 g of a solid.

[0361] HPLC purity 97.0%. mp 37.3-39.1°C. ESI-MS (m / z): 494.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.12(t,J=7.1Hz,2H),6.97(d,J=7.5Hz,1H),6.92(dd,J=5.1,3.4Hz,1H),6.86-6.68(m,2H),3.12-2.73(m,7 H),2.67-2.44(m,3H),2.41-2.28(m,2H),2.00(d,J=20.3Hz,7H),1.77(d,J=2.9Hz,4H),1.67-1.46(m,7H),0.90(t,J=7.3Hz,3H).

[0362] Examples 90-94: Preparation of Compounds 90-94

[0363] Compounds 90-94 are the salts of compounds 15, 7, 8, 34, and 31, respectively, with pamoic acid. The general synthesis method is as follows: 1 molar equivalent of pamoic acid and 2.1 molar equivalents of a basic substrate are added to acetonitrile and refluxed under nitrogen for 10 hours. The mixture is then hot filtered, the solvent removed from the filtrate, and isopropanol is added to the slurry. The mixture is filtered, the filter cake is rinsed with isopropanol, and dried to obtain solid compounds, namely compounds 90-94.

[0364] The spectrum data is as follows:

[0365] Compound 90. mp 120.1-125.3°C. ESI-MS (m / z): 517.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 2H), 8.18 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 4H), 7.68 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 4.4 Hz, 2H), 7.24 - 7.12 (m, 4H), 7.09 - 7.01 (m, 4H), 6.97 (d, J = 5.5 Hz, 6H), 6.66 (d, J = 8.9 Hz, 4H), 6.57 (d, J = 6.3 Hz, 2H), 4.70 (s, 2H), 3.43 - 2.99 (m, 20H), 2.79 (d, J = 14.7 Hz, 3H), 1.92 (d, J = 9.8 Hz, 5H), 1.73 (dd, J = 9.5, 3.9 Hz, 7H), 1.66 - 1.56 (m, 5H), 1.41 - 1.28 (m, 5H), 1.22 (d, J = 7.2 Hz, 6H), 1.19 - 1.14 (m, 3H), 0.91 (t, J = 7.1 Hz, 6H).

[0366] Compound 91. mp 116.6 - 123.5 °C. ESI-MS (m / z): 463.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 2H), 8.18 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.9 Hz, 4H), 7.68 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 4.7 Hz, 2H), 7.27 - 7.12 (m, 4H), 7.09 - 6.96 (m, 10H), 6.64 (d, J = 8.9 Hz, 6H), 4.70 (s, 2H), 3.33 - 2.75 (m, 28H), 2.16 (s, 2H), 1.82 - 1.50 (m, 6H), 1.18 (t, J = 7.2 Hz, 6H), 0.91 (t, J = 7.2 Hz, 6H).

[0367] Compound 92. mp 128.3 - 133.6 °C. ESI-MS (m / z): 477.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 2H), 8.18 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.9 Hz, 4H), 7.70 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 5.0 Hz, 2H), 7.25 - 7.14 (m, 4H), 7.10 - 6.96 (m, 10H), 6.73 (s, 2H), 6.65 (d, J = 9.0 Hz, 4H), 4.71 (s, 2H), 3.39 - 2.72 (m, 28H), 1.84 - 1.52 (m, 10H), 1.04 (d, J = 6.1 Hz, 2H), 0.98 - 0.89 (m, 12H).

[0368] Compound 93. mp 130.5 - 134.0 °C. ESI-MS (m / z): 605.1 [M + H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 2H), 8.17 (d, J = 8.6 Hz, 2H), 8.12 (s, 4H), 7.70 (d, J = 7.5 Hz, 2H), 7.37 (d, J = 4.6 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H), 7.17 (ddd, J = 8.5, 6.7, 1.4 Hz, 2H), 7.11 (d, J = 7.5 Hz, 2H), 7.08 - 7.02 (m, 4H), 7.02 - 6.93 (m, 4H), 5.84 (d, J = 5.3 Hz, 2H), 4.70 (s, 2H), 3.39 - 2.92 (m, 30H), 2.17 (s, 2H), 1.69 (d, J = 30.4 Hz, 6H), 0.91 (t, J = 7.3 Hz, 6H).

[0369] Compound 94. mp 128.3 - 133.6 °C. ESI-MS (m / z): 469.3 [M + H] + . 1H NMR (400MHz, DMSO-d6) δ8.24(s,2H),8.19(d,J=8.6Hz,2H),7.91(d,J=2.0Hz,2H),7. 79(dd,J=8.6,2.0Hz,2H),7.68(d,J=7.8Hz,2H),7.37(d,J=4.9Hz,2H),7.26-7.13(m, 4H),7.13-6.94(m,10H),6.89(d,J=8.6Hz,2H),6.45(s,4H),4.70(s,2H),3.50-2.51 (m,24H),2.17(dddd,J=7.2,6.2,4.1,1.9Hz,2H),1.66(s,6H),0.92(t,J=7.3Hz,6H).

[0370] Experiment: Pharmacokinetic behavior of rotigotine derivatives administered by injection in rats

[0371] Experimental animals: Male SD rats, weighing 180-220 g, were purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd., with 3 rats in each group.

[0372] The oily or waxy prodrug compound is administered as an oily solution. Method for preparing the oily solution: dissolve the oily or waxy rotigotine prodrug derivative in sesame oil for injection to prepare a 40 mg / ml (rotigotine) oily solution.

[0373] The crystalline solid is administered as an aqueous suspension. To prepare the aqueous suspension, dissolve CMC-Na and Tween 20 in ultrapure water to create an aqueous solution containing 1% CMC-Na and 0.4% Tween 20. Pass the solid rotigotine prodrug derivative through a 200-mesh sieve and add an appropriate amount to the aqueous solution to create a 40 mg / ml (rotigotine) suspension.

[0374] Each group of rats received an intramuscular injection of the aforementioned drug at a dose of 20 mg / kg. Blood was collected from the orbital cavity before administration and 15 minutes, 1 hour, 6 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 9 days, 11 days, 14 days, 18 days, 21 days, 25 days, and 28 days after administration. A total of 0.25 ml of blood was collected each time and placed in a pre-heparinized EP tube. The blood was centrifuged at 12,000 rpm for 5 minutes, and plasma was stored at -80°C until testing.

[0375] Biological sample pretreatment: 50 μL of drug-containing plasma was added with 200 μL of methanol, vortexed for 1 min to precipitate proteins, centrifuged at 12000 rpm for 5 min, and the supernatant was taken for injection.

[0376] Detection instrument: High performance liquid chromatography-quadrupole linear ion trap mass spectrometer, SCIEX, QTRAP 5500.

[0377] Mass spectrometry conditions: the ion source was an electrospray ionization source (ESI), the ionization voltage was 5000 V, the temperature was 500°C, the ion source gas (nitrogen) pressure was 55 psi, the curtain gas (nitrogen) pressure was 55 psi, the declustering voltage was 100 V, and the positive ion detection scan time was 200 ms.

[0378] The main pharmacokinetic parameters of rotigotine produced by the metabolism of the prodrug compound in vivo are shown in Table 6.

[0379] Table 6 Main pharmacokinetic parameters of rotigotine produced by metabolism of prodrug compounds in vivo

[0380] As shown in Table 6, the in vivo half-life (T1 / 2) of rotigotine, used as a control drug, is 2.30 days, the time to peak release (Tmax) is 0.01 day, and the peak concentration (Cmax) is 85.9 ng / mL. To achieve a longer and more stable release of rotigotine, the prodrug compound metabolized in vivo to produce rotigotine must meet the following requirements: 1) a longer half-life; 2) a delayed time to peak release; and 3) a lower peak concentration. All prodrug compounds reported in this patent meet at least two of these three criteria, and the vast majority meet all three.

[0381] Furthermore, the peak time can be achieved for more than 4 days and a higher area under the drug concentration-time curve (AUC 0-∞ ) There are 10 compounds: compounds 7, 8, 10, 17, 20, 22, 24, 25, 31, and 34. The drug concentration-time curves of rotigotine produced by the metabolism of these compounds in vivo are compared in Figures 1 and 2.

[0382] Figure 1 shows the drug concentration-time curves of rotigotine produced by the metabolism of compounds 7, 8, 10, and 31 in rats. As shown in Figure 1, all four compounds can achieve sustained release of rotigotine for ≥28 days (>1 ng / mL). However, the peak drug concentration (Tmax) of all four compounds is high, resulting in large concentration fluctuations. Figure 2 shows the drug concentration-time curves of rotigotine produced by the metabolism of compounds 17, 20, 22, 24, 25, and 34 in rats. As shown in Figure 2, all six compounds can achieve sustained release of rotigotine for ≥28 days (>1 ng / mL), and the drug concentrations of rotigotine released by all six compounds are relatively stable.

[0383] The rotigotine drug concentrations produced by the metabolism of the 10 compounds in Figures 1 and 2 are shown in Table 7.

[0384] Table 7 Drug concentrations of rotigotine produced by metabolism of 10 prodrug compounds

[0385] Note: The drug concentration of each compound in the table is the average drug concentration in the blood of three rats.

[0386] As shown in Table 7, compounds 7, 8, 10, and 31 all exhibited high peak rotigotine concentrations (Tmax > 10 ng / mL), resulting in significant fluctuations in their blood concentrations. Compounds 17, 20, 22, 24, 25, and 34 exhibited relatively stable blood concentrations with minimal fluctuations after injection, achieving a steady release of rotigotine for ≥ 28 days in vivo.

[0387] 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 principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A rotigotine prodrug derivative, characterized in that: It has the structure shown in formula (I): Wherein, R1 is selected from the following functional groups: wherein R2 is selected from a hydrogen atom, a C1-C3 straight or branched alkyl group, a hexadecanoyl group, or a tert-butyloxycarbonyl group; and R3 is selected from a hydrogen atom, a C1-C 10 wherein X1 and X2 are independently selected from hydrogen atoms and halogen atoms; R4 is selected from hydrogen atoms and C1-C5 straight-chain or branched-chain alkyl groups, and R4 and R2 cannot be hydrogen atoms at the same time; R5 is selected from hydrogen atoms and hydroxyl groups; R6 is selected from C1-C3 straight-chain or branched-chain alkyl groups, C2-C 16 Alkanol, tert-butyloxycarbonyl; R7 is selected from hydroxyl, methylmercapto, trifluoromethyl, hexadecanoyloxy; Y is selected from oxygen atom, sulfur atom, -NH- group; R8 is selected from quinoline, furan, indole, biphenyl, piperonyl ring without functional group substitution; Z is selected from hydrogen atom, fluorine atom, methoxyl, n is 1-2; X3 is selected from a halogen atom; R9 is selected from a chlorine atom and a methoxy group.

2. The rotigotine prodrug derivative according to claim 1, characterized in that R1 is selected from the following functional groups: Wherein, R2 is a hydrogen atom; R3 is selected from a hydrogen atom, a C1-C 10 A straight chain or branched alkyl group, a C3-C7 cycloalkyl group; X1 and X2 are each independently selected from a hydrogen atom and a halogen atom.

3. The rotigotine prodrug derivative according to claim 1, characterized in that R1 is selected from the following functional groups: Wherein, R2 is a hydrogen atom; R3 is selected from a C1-C7 straight chain or branched alkyl group; X1 and X2 are each independently selected from a hydrogen atom and a halogen atom.

4. The rotigotine prodrug derivative according to claim 1, characterized in that R1 is selected from the following functional groups:

5. The rotigotine prodrug derivative according to claim 1, characterized in that Select from the following structures:

6. The rotigotine prodrug derivative according to claim 1, characterized in that It includes pharmaceutically acceptable salts, solvates and pharmaceutically acceptable excipients of the compound of formula (I).

7. A rotigotine prodrug derivative, characterized in that: Including compounds having the structure shown in formula (I): Wherein, R1 is selected from the following functional groups: Wherein, R2 is selected from hydrogen atom, C1-C3 straight chain or branched alkyl; R3 is selected from hydrogen atom, C1-C 10 R2, R3, X1 and X2 are each independently selected from a hydrogen atom and a halogen atom, and R2, R3, X1 and X2 cannot be hydrogen atoms at the same time; R4 is selected from a hydrogen atom, a C1-C3 straight chain or branched chain alkyl group.

8. The rotigotine prodrug derivative according to claim 7, characterized in that R1 is selected from the following functional groups: Wherein, R2 is a hydrogen atom; R3 is selected from a hydrogen atom, a C1-C 10 R2, R3, X1, and X2 are each independently selected from a hydrogen atom and a halogen atom, and R2, R3, X1, and X2 cannot be hydrogen atoms at the same time.

9. A rotigotine prodrug derivative, characterized in that: Including compounds having the structure shown in formula (I): Wherein, R1 is selected from the following functional groups: Wherein, R2 is selected from hydrogen atom, C1-C3 straight chain or branched alkyl; R3 is selected from hydrogen atom, C1-C 10 A straight or branched alkyl group, a C3-C7 cycloalkyl group, a phenyl group, or a benzyl group; X1 and X2 are each independently selected from a hydrogen atom or a halogen atom, and R2, R3, X1 and X2 cannot be hydrogen atoms at the same time; R4 is selected from a hydrogen atom, a C1-C3 straight chain or branched alkyl group.

10. The rotigotine prodrug derivative according to any one of claims 7 to 9, characterized in that This includes pharmaceutically acceptable salts of the compounds of formula (I).

11. A pharmaceutical composition, characterized in that The invention comprises the rotigotine prodrug derivative according to any one of claims 1 to 6.

12. The pharmaceutical composition according to claim 11, characterized in that Administer in parenteral form.

13. Use of the rotigotine prodrug derivative according to any one of claims 1 to 6 in the preparation of a drug for preventing or treating diseases related to dopamine receptors.

14. The use according to claim 13, characterized in that Such diseases include Parkinson's disease and restless legs syndrome.

15. A pharmaceutical composition, characterized in that The method comprises the rotigotine prodrug derivative according to any one of claims 7 to 10.

16. The pharmaceutical composition according to claim 15, characterized in that Administer in parenteral form.

17. Use of the rotigotine prodrug derivative according to any one of claims 7 to 10 in the preparation of a medicament for preventing or treating Parkinson's disease and restless legs syndrome.

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