Aminoquinoline derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of radiopharmaceutical labeling, and particularly relates to an aminoquinoline derivative as well as a preparation method and application thereof. The aminoquinoline derivative provided by the invention has a structure as shown in a formula 1: # imgabs0, R1 is halogen or hydrogen, R2 is # imgabs1 # imgabs2 #, X is carbon or nitrogen, and Y is carbon or nitrogen. The aminoquinoline derivative provided by the invention has high selectivity and excellent affinity to Tau protein, and can be used as a Tau protein aggregate selective ligand. According to the present invention, with the application of the aminoquinoline derivative as the tracer agent, the tau protein can have the good imaging effect, and the potential molecular probe is provided for the Alzheimer's disease (AD) diagnosis.

Description

Technical Field

[0001] The present invention belongs to the technical field of biochemical detection, and particularly relates to an aminoquinoline derivative, a preparation method thereof, and an application thereof. Background Art

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disease, and its main pathological features include plaques formed by the deposition of amyloid-beta (Aβ) and neurofibrillary tangles formed by the aggregation of abnormally phosphorylated tau protein. Certain progress has been made in the research on PET tracers for Aβ plaques, but the imaging technology for tau protein has always been a challenge in AD research. The abnormal aggregation of tau protein is closely related to neuronal damage and cognitive function decline. Therefore, developing a PET tracer that can specifically label tau protein is of great significance for early diagnosis, disease progression monitoring, and treatment effect evaluation.

[0003] With the development of radiochemistry and molecular imaging, researchers have developed a variety of tau protein PET tracers. These tracers mainly target different binding sites on tau protein, such as the microtubule binding domain, N-terminal region, and C-terminal region. Among them, some tracers have entered the clinical trial stage and shown signals consistent with tau protein aggregation in the brains of AD patients. These findings provide the possibility of directly observing tau protein pathology through PET imaging technology in the future, and are expected to bring new breakthroughs in the diagnosis and treatment of AD. Currently, including the first-generation 11 11C-PBB3, 18 18F-THK5351, 18 18F-T807, 18 18F-T808 and the second-generation 18 18F-MK-6240, 18 18F-RO-948, 18 18F-PI-2620, 18 18F-GTP1, 18 18F-PBB3, 18 18F-JNJ311 and 18 18F-JNJ067 and other PET ligands have been applied to test PHFs in the brains of AD patients. Compared with the first-generation imaging agents, the affinity and selectivity of the second-generation TauPET imaging agents have been greatly improved. However, in order to obtain more accurate detection results, TauPET imaging agents with better selectivity, higher affinity, and better imaging effects are needed. Summary of the Invention

[0004] In view of this, the present invention provides an aminoquinoline derivative, a preparation method and an application thereof. The aminoquinoline derivative provided by the present invention has excellent affinity and selectivity for tau protein, and can make the tau protein have better imaging effect as a tracer.

[0005] In order to solve the above technical problems, the present invention provides an aminoquinoline derivative having the structure shown in Formula 1:

[0006]

[0007] Wherein, R1 is halogen or hydrogen, and R2 is

[0008] X is carbon or nitrogen, and Y is carbon or nitrogen.

[0009] Preferably, when X is carbon, Y is nitrogen, R1 is -F, and R2 is

[0010] When X is nitrogen, Y is carbon, R1 is -F, and R2 is

[0011] Preferably, it has any one of the structures shown in D1 - D7:

[0012]

[0013] The present invention also provides a preparation method of the aminoquinoline derivative described in the above technical solution, including the following steps:

[0014] Mix compound 1, compound 2, a basic compound, a ligand, a catalyst and a first organic solvent, and carry out Buchwald-Hartwig coupling reaction to obtain the aminoquinoline derivative;

[0015] Compound 1 has the structure shown in Formula a, and compound 2 has the structure shown in Formula b:

[0016]

[0017] Wherein R1 is halogen or hydrogen, and R2 is

[0018] X is carbon or nitrogen, and Y is carbon or nitrogen.

[0019] Preferably, the molar ratio of compound 1 to compound 2 is 1:0.5 - 1.5.

[0020] Preferably, the basic compound includes potassium phosphate, sodium tert-butoxide, lithium bis(trimethylsilyl)amide, cesium carbonate, sodium bis(trimethylsilyl)amide, potassium tert-butoxide, potassium carbonate or sodium carbonate;

[0021] The molar ratio of the compound 1 to the basic compound is 1:0.5-5;

[0022] The ligand includes 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, methanesulfonate (4,5-bis(diphenylphosphine)-9,9-dimethylxanthene) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II), chloro[(4,5-bis(diphenylphosphine)-9,9-dimethylxanthene)-2-(2-aminobiphenyl)] palladium (II), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine)-ferrocene or tri-tert-butylphosphine;

[0023] The molar ratio of the compound 1 to the ligand is 1:0.01-0.1.

[0024] Preferably, the catalyst comprises tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, tris(bisbenzylideneacetone)dipalladium, palladium acetate or ditriphenylphosphinepalladium dichloride;

[0025] The first organic solvent includes tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, acetonitrile, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylacetamide, m-xylene, toluene, xylene, 1,2-dimethoxyethane;

[0026] The molar ratio of the compound 1 to the catalyst is 1:0.01-0.1.

[0027] Preferably, the temperature of the Buchwald-Hartwig coupling reaction is 80-100° C. and the time is 5-16 hours.

[0028] Preferably, the Buchwald-Hartwig coupling reaction further comprises the following steps:

[0029] The system after the Buchwald-Hartwig coupling reaction is concentrated and then dissolved in a second organic solvent, the solution obtained by the dissolution is extracted, and the organic phase is collected;

[0030] The organic phase is separated and purified by silica gel column chromatography to obtain the aminoquinoline derivative;

[0031] The second organic solvent includes ethyl acetate, dichloromethane, ether, petroleum ether or methyl tert-butyl ether;

[0032] The extraction agent for extraction includes saturated salt water;

[0033] The eluent used for separation and purification by the silica gel chromatography column is a mixed solution of dichloromethane and methanol; the volume ratio of the dichloromethane to methanol is 10 to 50:1.

[0034] The present invention also provides the use of the aminoquinoline derivative described in the above technical solution or the aminoquinoline derivative prepared by the preparation method described in the above technical solution in the preparation of a Tau protein PET tracer.

[0035] The present invention provides an aminoquinoline derivative having the structure shown in Formula 1: Wherein, R1 is a halogen or hydrogen, and R2 is X is carbon or nitrogen, and Y is carbon or nitrogen. The aminoquinoline derivative provided by the present invention has high selectivity and excellent affinity for Tau protein and can be used as a selective ligand for Tau protein aggregates. The aminoquinoline derivative provided by the present invention can make the tau protein have a better imaging effect as a tracer, providing a potential molecular probe for the diagnosis of Alzheimer's disease (AD). BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 1H NMR spectrum of D1 prepared in Example 1; 1 1H NMR spectrum;

[0037] Figure 2 1H NMR spectrum of D2 prepared in Example 1; 1 1H NMR spectrum;

[0038] Figure 3 1H NMR spectrum of D3 prepared in Example 1; 1 1H NMR spectrum;

[0039] Figure 4 1H NMR spectrum of D4 prepared in Example 1; 1 1H NMR spectrum;

[0040] Figure 5 1H NMR spectrum of D5 prepared in Example 1; 1 1H NMR spectrum;

[0041] Figure 6 1H NMR spectrum of D6 prepared in Example 1; 1 1H NMR spectrum;

[0042] Figure 7 1H NMR spectrum of D7 prepared in Example 1; 1 1H NMR spectrum. DETAILED DESCRIPTION OF THE INVENTION

[0043] The present invention provides an aminoquinoline derivative having the structure shown in Formula 1:

[0044]

[0045] Among them, R1 is a halogen or hydrogen, and the halogen can be -F, -Cl, -Br or -I; R2 is

[0046] X is carbon or nitrogen, and Y is carbon or nitrogen.

[0047] In the present invention, the substitution site of R1 in formula 1 can be any carbon in the ring containing Y and the ring containing X; the substitution site of -NH-R2 can be any carbon in the ring containing Y and the ring containing X.

[0048] As a specific embodiment of the present invention, when X is carbon, Y is nitrogen, R1 is -F, and R2 can be When X is nitrogen, Y is carbon, R1 can be -F, and R2 is

[0049] As a specific embodiment of the present invention, the aminoquinoline derivative can have any one of the structures shown in D1 to D7:

[0050]

[0051] The present invention also provides a preparation method of the aminoquinoline derivative described in the above technical solution, including the following steps:

[0052] Mix compound 1, compound 2, a basic compound, a ligand, a catalyst and a first organic solvent, and carry out Buchwald-Hartwig coupling reaction to obtain the aminoquinoline derivative;

[0053] Compound 1 has the structure shown in formula a, and compound 2 has the structure shown in formula b:

[0054]

[0055] Among them, R1 is a halogen or hydrogen, and R2 X is carbon or nitrogen, and Y is carbon or nitrogen.

[0056] In the present invention, the substitution site of R1 in formula a can be any carbon in the ring containing Y and the ring containing X; the substitution site of -Br can be any carbon in the ring containing Y and the ring containing X.

[0057] As a specific embodiment of the present invention, the mixing can include the following steps:

[0058] Dissolve compound 1 and compound 2 in the first organic solvent to obtain a mixed solution;

[0059] Add a basic compound, a ligand and a catalyst to the mixed solution.

[0060] As a specific embodiment of the present invention, the compound 1 can be The compound 2 can be

[0061] As a specific embodiment of the present invention, the molar ratio of compound 1 to compound 2 can be 1:0.5-1.5, or 1:1-1.3.

[0062] As a specific embodiment of the present invention, the alkaline compound may include potassium phosphate (K3PO4), sodium tert-butoxide, lithium bis(trimethylsilyl)amide (LHMDS), cesium carbonate (Cs2CO3), sodium bis(trimethylsilyl)amide, potassium tert-butoxide, potassium carbonate (K2CO3) or sodium carbonate (Na2CO3); the molar ratio of the compound 1 to the alkaline compound may be 1:0.5-5, or 1:3-4.

[0063] As a specific embodiment of the present invention, the ligand may include 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (XantPhos), methanesulfonic acid (4,5-bis(diphenylphosphine)-9,9-dimethylxanthene) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (XantPhos Pd G4), chloro[(4,5-bis(diphenylphosphine)-9,9-dimethylxanthene)-2-(2-aminobiphenyl)] palladium (II) (XantPhos Pd G2), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) ferrocene or tri-tert-butylphosphine (P(t-Bu)3); the molar ratio of the compound 1 to the ligand may be 1:0.01 to 0.1, or 1:0.05 to 0.08.

[0064] As a specific embodiment of the present invention, the catalyst includes tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), tetrakis(triphenylphosphine)palladium, tris(bisbenzylideneacetone)dipalladium, palladium acetate or ditriphenylphosphine palladium dichloride; the molar ratio of the compound 1 to the catalyst can be 1:0.01 to 0.1, and can also be 1:0.05 to 0.08.

[0065] As a specific embodiment of the present invention, the first organic solvent may include tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, acetonitrile, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylacetamide, m-xylene, toluene, xylene, 1,2-dimethoxyethane. As a specific embodiment of the present invention, the mass ratio of the compound 1 to the volume ratio of the first organic solvent can be 18-22 mg:1 mL, and can also be 20 mg:1 mL.

[0066] As a specific embodiment of the present invention, the temperature of the Buchwald-Hartwig coupling reaction can be 80 to 100 °C, or can also be 80 to 90 °C; the time of the Buchwald-Hartwig coupling reaction can be 5 to 16 h, or can also be 5 to 10 h. As a specific embodiment of the present invention, the Buchwald-Hartwig coupling reaction can be carried out in a protective atmosphere, and the protective atmosphere can be nitrogen.

[0067] As a specific embodiment of the present invention, taking tetrahydrofuran (THF) as the first organic solvent, XantPhos as the ligand, Pd2(dba)3 as the catalyst, and K3PO4 as the basic compound as an example, the equation of the Buchwald-Hartwig coupling reaction is as follows:

[0068]

[0069] As a specific embodiment of the present invention, after the Buchwald-Hartwig coupling reaction, the following steps are further included:

[0070] Concentrate the system after the Buchwald-Hartwig coupling reaction and dissolve it in a second organic solvent, extract the obtained solution, and collect the organic phase;

[0071] Perform silica gel column chromatography separation and purification on the organic phase to obtain the aminoquinoline derivative.

[0072] In the present invention, the system after the Buchwald-Hartwig coupling reaction is concentrated and then dissolved in a second organic solvent, and the obtained solution is extracted to collect the organic phase. As a specific embodiment of the present invention, the concentration can be vacuum distillation; the present invention has no special requirements for the vacuum distillation, as long as the solvent in the system can be removed. As a specific embodiment of the present invention, the second organic solvent can include ethyl acetate, dichloromethane, ether, petroleum ether or methyl tert-butyl ether; the present invention has no special requirements for the dissolution, as long as it can be completely dissolved.

[0073] As a specific embodiment of the present invention, the extractant for extraction can include saturated brine; the number of extractions can be 2 to 4 times, or can also be 3 times; the organic phases obtained from each extraction are combined.

[0074] After obtaining the organic phase, the present invention separates and purifies the organic phase by a silica gel column chromatography to obtain the aminoquinoline derivative. As a specific embodiment of the present invention, the eluent for the silica gel column chromatography separation and purification can be a mixed solution of dichloromethane and methanol; the volume ratio of dichloromethane to methanol can be 10-50:1, and can also be 20-40:1. As a specific embodiment of the present invention, the aminoquinoline derivative is a pale yellow solid.

[0075] The present invention also provides the use of the aminoquinoline derivative described in the above technical solution or the aminoquinoline derivative prepared by the preparation method described in the above technical solution in the preparation of a Tau protein PET tracer.

[0076] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below in conjunction with examples, but they cannot be understood as limiting the protection scope of the present invention.

[0077] Example 1

[0078] Dissolve compound 1 (100 mg, 1.0 eq) and compound 2 (63 mg, 1.0 eq) in 5 mL of anhydrous tetrahydrofuran; add K3PO4 (187 mg, 3.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (25 mg, 0.05 eq), and tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (40 mg, 0.05 eq) to the resulting solution under stirring, and then carry out a 5 h Buchwald-Hartwig coupling reaction at 80 °C under a nitrogen protection atmosphere; after the reaction is completed, concentrate under reduced pressure to remove the reaction solvent, add 30 mL of ethyl acetate to dissolve the product of the Buchwald-Hartwig coupling reaction, and then mix with 30 mL of saturated brine for extraction, and collect the organic phase; repeat the extraction 3 times and then combine the organic phases; carry out silica gel column chromatography separation and purification on the combined organic phase (the volume ratio of dichloromethane to methanol is 20:1) to obtain a pale yellow solid aminoquinoline derivative.

[0079] The specific structures of the selected compound 1 and compound 2 and the specific structure of the prepared aminoquinoline derivative are listed in Table 1.

[0080] Table 1 Structural formulas of the raw materials and products selected in Example 1, as well as the purity and yield of the products

[0081]

[0082] The aminoquinoline derivatives D1-D7 prepared in the examples were subjected to 1H nuclear magnetic resonance detection, and the following detection results were obtained. The obtained 1 1H NMR spectrum is as Figures 1 to 7As shown; it can be seen from the results that the aminoquinoline derivatives prepared in the examples have the structures shown in Table 1.

[0083] D1: 89 mg of pale yellow solid, yield 44%, HPLC purity = 96.46%. 1 HNMR(400MHz, DMSO-d6) δ 9.33(s, 1H), 8.91(s, 1H), 8.71 - 8.62(m, 1H), 8.52(d, J = 5.9Hz, 1H), 8.11(d, J = 8.3Hz, 1H), 8.02(d, J = 6.0Hz, 1H), 7.80(dd, J = 21.0, 7.8Hz, 2H), 7.65(t, J = 7.8Hz, 1H), 7.51 - 7.36(m, 2H), 7.15(d, J = 2.0Hz, 1H).

[0084] D2: 74 mg of yellow solid, yield 37%, HPLC purity = 97.23%. 1 HNMR(400MHz, DMSO-d6) δ 9.28(s, 1H), 9.08(s, 1H), 8.74(dd, J = 4.1, 1.5Hz, 1H), 8.32(dd, J = 17.1, 7.1Hz, 2H), 8.02(d, J = 8.9Hz, 1H), 7.64(dd, J = 13.3, 4.0Hz, 3H), 7.57 - 7.42(m, 3H).

[0085] D3: 93 mg of yellow solid, yield 46%, HPLC purity = 97.34%. 1 HNMR(400MHz, DMSO-d6) δ 8.90(s, 1H), 8.72(dd, J = 4.1, 1.3Hz, 1H), 7.98(s, 1H), 7.78(d, J = 8.2Hz, 2H), 7.71(dd, J = 13.1, 2.2Hz, 1H), 7.65 - 7.55(m, 2H), 7.51(dd, J = 8.4, 4.1Hz, 1H), 6.61(t, J = 7.0Hz, 1H).

[0086] D4: 58 mg of yellow solid, yield 29%, HPLC purity = 99.40%. 1HNMR(400MHz, DMSO-d6) δ 9.41 (s, 1H), 8.48 (d, J = 5.9 Hz, 1H), 8.39 (dd, J = 10.8, 2.7 Hz, 1H), 8.30 (d, J = 5.3 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.97 (dd, J = 9.2, 5.8 Hz, 1H), 7.86 - 7.68 (m, 3H), 7.63 (td, J = 8.9, 2.7 Hz, 1H), 6.19 (d, J = 5.3 Hz, 1H).

[0087] D5: Pale yellow solid, 86 mg, yield 43%, HPLC purity = 99.88%. 1 HNMR(400MHz, DMSO-d6) δ 8.95 (dd, J = 4.1, 1.5 Hz, 1H), 8.40 (dd, J = 10.9, 2.7 Hz, 1H), 8.36 - 8.25 (m, 2H), 8.08 - 7.90 (m, 2H), 7.90 - 7.79 (m, 1H), 7.69 - 7.58 (m, 2H), 7.50 (dd, J = 8.5, 4.1 Hz, 1H), 6.21 (d, J = 5.3 Hz, 1H).

[0088] D6: Yellow solid, 95 mg, yield 47%, HPLC purity = 99.87%. 1 HNMR(400MHz, DMSO-d6) δ 9.30 (s, 1H), 9.19 (s, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.41 (d, J = 5.7 Hz, 1H), 8.22 (dd, J = 10.8, 2.7 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.02 (dd, J = 9.2, 5.8 Hz, 1H), 7.78 (s, 1H), 7.75 - 7.60 (m, 3H), 7.38 (d, J = 5.0 Hz, 1H).

[0089] D7: Yellow solid, 89 mg, yield 44%, HPLC purity = 99.83%. 1 HNMR(400MHz, DMSO-d6) δ 8.46 (d, J = 5.2 Hz, 1H), 8.41 (d, J = 6.7 Hz, 1H), 8.28 (dd, J = 10.9, 2.7 Hz, 1H), 8.05 - 7.94 (m, 2H), 7.82 - 7.73 (m, 1H), 7.66 - 7.52 (m, 2H), 7.18 (t, J = 6.5 Hz, 1H), 6.91 (t, J = 7.0 Hz, 1H), 6.76 (d, J = 5.2 Hz, 1H).

[0090] Determination of the affinity for Tau protein aggregates:

[0091] Experimental method for affinity determination: K18Δ280-Tau has a complete microtubule-binding domain, and a competitive binding assay was performed using K18Δ280-Tau. Aβ was prepared according to the method reported in the literature "Synthesis and Evaluation of Fluorine-18 Labeled 2-Phenylquinoxaline Derivatives as Potential Tau Imaging Agents" 1-42 and K18Δ280-Tau aggregates; then the mixture of Aβ 1-42 aggregates or K18Δ280-Tau aggregates and the test compound was placed in a black 96-well plate and gently shaken and cultured at 37 °C for 30 min. The fluorescence intensity of each well was obtained using an Infinite M200pro microplate reader. The excitation / emission wavelengths of Aβ 1-42 aggregates were 540 nm and 632 nm, respectively, and the excitation / emission wavelengths of K18-Tau aggregates were 524 nm and 654 nm, respectively. The fluorescence signals of all test compounds were also measured in the same way to reduce the background in the detection. All data were input into GraphPad Prism 8.0 software, and the inhibitor constant (Ki) value was calculated according to the Cheng-Prusoff equation. The results are listed in Table 2. The binding affinity of the probe was determined by competing AD brain homogenate with the reference ligands PBB3 and ThT. PBB3 is for the binding site on Tau aggregates, and ThT is for the binding site on Aβ plaques.

[0092] Table 2 Results of the affinity of compounds for aggregated Tau protein

[0093]

[0094] Among them, "-" indicates that no binding force between the compound and the protein was detected. The results were measured by three independent experiments, and the values are the averages.

[0095] The Ki value and IC 50 value show the affinity of the compound for Tau protein. The smaller the value, the higher the affinity; the selectivity represented by the selection multiple means the higher the value, the better the selectivity. It can be seen from Table 2 that the aminoquinoline derivatives provided by the present invention have excellent selectivity for Tau. Among them, the affinity of compound D7 for Tau is 4.89 nM, the affinity for Aβ is 145.05 nM, and the selectivity is 145.05, showing outstanding selectivity for Tau.

[0096] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. People can also obtain other embodiments based on these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. An aminoquinoline derivative, characterized in that It has the structure shown in formula 1: Wherein, R1 is halogen or hydrogen, R2 is X is carbon or nitrogen, and Y is carbon or nitrogen.

2. The aminoquinoline derivative according to claim 1, characterized in that When X is carbon, Y is nitrogen, R1 is -F, and R2 is When X is nitrogen, Y is carbon, R1 is -F, and R2 is 3. The aminoquinoline derivative according to claim 1, characterized in that Having any structure shown in D1 to D7:

4. The method for preparing the aminoquinoline derivative according to any one of claims 1 to 3, characterized in that: The following steps are involved: Mixing compound 1, compound 2, a basic compound, a ligand, a catalyst and a first organic solvent, and performing a Buchwald-Hartwig coupling reaction to obtain the aminoquinoline derivative; The compound 1 has a structure shown in formula a, and the compound 2 has a structure shown in formula b: Wherein R1 is halogen or hydrogen, R2 is X is carbon or nitrogen, and Y is carbon or nitrogen.

5. The preparation method according to claim 4, characterized in that: The molar ratio of the compound 1 to the compound 2 is 1:0.5-1.

5.

6. The preparation method according to claim 4, characterized in that: The alkaline compound includes potassium phosphate, sodium tert-butoxide, lithium bis(trimethylsilyl)amide, cesium carbonate, sodium bis(trimethylsilyl)amide, potassium tert-butoxide, potassium carbonate or sodium carbonate; The molar ratio of the compound 1 to the basic compound is 1:0.5-5; The ligand includes 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, methanesulfonate (4,5-bis(diphenylphosphine)-9,9-dimethylxanthene) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II), chloro[(4,5-bis(diphenylphosphine)-9,9-dimethylxanthene)-2-(2-aminobiphenyl)] palladium (II), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine)-ferrocene or tri-tert-butylphosphine; The molar ratio of the compound 1 to the ligand is 1:0.01-0.

1.

7. The preparation method according to claim 4, characterized in that: The catalyst includes tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, tris(bisbenzylideneacetone)dipalladium, palladium acetate or ditriphenylphosphine palladium dichloride; The first organic solvent includes tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, acetonitrile, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylacetamide, m-xylene, toluene, xylene, 1,2-dimethoxyethane; The molar ratio of the compound 1 to the catalyst is 1:0.01-0.

1.

8. The preparation method according to claim 4, characterized in that: The temperature of the Buchwald-Hartwig coupling reaction is 80-100° C. and the time is 5-16 hours.

9. The preparation method according to claim 4 or 8, characterized in that: The Buchwald-Hartwig coupling reaction further comprises the following steps: The system after the Buchwald-Hartwig coupling reaction is concentrated and then dissolved in a second organic solvent, the solution obtained by the dissolution is extracted, and the organic phase is collected; The organic phase is separated and purified by silica gel column chromatography to obtain the aminoquinoline derivative; The second organic solvent includes ethyl acetate, dichloromethane, ether, petroleum ether or methyl tert-butyl ether; The extraction agent for extraction includes saturated salt water; The eluent used for separation and purification by the silica gel chromatography column is a mixed solution of dichloromethane and methanol; the volume ratio of the dichloromethane to methanol is 10 to 50:

1.

10. Use of the aminoquinoline derivative according to any one of claims 1 to 3 or the aminoquinoline derivative prepared by the preparation method according to any one of claims 4 to 9 in the preparation of a Tau protein PET tracer.

Images