Preparation method of < 18 > F-DOPA and F-18 labeled precursor of < 18 > F-DOPA

Abstract

The invention relates to the technical field of biological medicines, in particular to a preparation method of 18F-DOPA and an F-18 labeled precursor of 18F-DOPA. The structural formula of the F-18 labeled phenolic precursor compound is as shown in a formula I: # imgabs0 #; wherein R1 and R2 are hydroxyl protecting groups; r3 is a leaving group; r4 and R5 are independently hydrogen or an amino protecting group; and R6 is a carboxyl protecting group. The invention provides a simple and efficient < 18 > F-DOPA preparation method, and particularly relates to preparation of < 18 > F-DOPA by constructing a key phenol precursor compound and performing a simple and efficient photocatalytic deoxidation fluorination reaction on aromatic hydrocarbon. The method has the advantages of few steps, high yield, simplicity and convenience in operation, good repeatability and good automatic production potential. The radioactive tracer agent 18F-DOPA synthesized by using the method has high specific activity, high chemical purity and high radioactive purity, and has an important value for clinical popularization of 18F-DOPA.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and specifically to a 18 The invention relates to a preparation method of F-DOPA and its F-18 labeled precursor. Background Art

[0002] 6-[18F]Fluoro-L-dopa ( 18 F-DOPA) is an analog of L-DOPA (L-DOAP). Its metabolic process in the body is similar to that of L-DOPA and can reflect the anabolism of L-DOPA in the body. 18 F-DOPA is a positron-emitting imaging agent for studying the function of dopamine in the brain. It has been widely used in the diagnosis of neurological diseases such as schizophrenia, Parkinson's disease, and Alzheimer's disease. 18 F-DOPA is widely used in the diagnosis of neuroendocrine tumors and has good imaging effects on well-differentiated neuroendocrine tumors of the gastrointestinal tract, neuroblastoma, medullary thyroid carcinoma, pheochromocytoma, paraganglioma, and malignant tumors of the central nervous system.

[0003] In the prior art, 18 The synthesis methods of F-DOPA include electrophilic F-18 substitution and nucleophilic F-18 substitution. 18 The electrophilic F-18 labeling method of F-DOPA requires the use of highly corrosive gases [ 18 F] F2 preparation device, obtained 18 The specific activity of F-DOPA needs to be improved. In addition, the preparation process of the labeling precursor used in this method is complicated and not resistant to storage. 18 Nucleophilic F-18 substituted precursors of F-DOPA are used 18 Preparation of F-DOPA, the nickel complex precursor developed by Ritter et al. can be quickly prepared 18 F-DOPA, but the precursor is complex to synthesize and unstable ( J. Am. Chem. Soc. 2012, 134, 42, 17456–17458). The nitro precursor developed by ABX is prepared by a three-step reaction. 18 F-DOPA (EP2746250A1, 2014). In addition, several aryl iodonium salts and borate ester precursors have been reported to be used for 18 F-DOPA can be prepared by photocatalytic isotope exchange, but this method has the disadvantages of low radiochemical yield, complex and unstable precursor synthesis, and complicated preparation process (J Nucl Med. 2015, 56(1): 106-112; Angew.Chem. Int. Ed., 53: 7751-7755). 18F-DOPA, however, the relatively low product specific activity will limit its wider clinical application (Nature Chemistry 2022, 14(2): 216-223; Organic Letters 2024; 26(20): 4308–4313).

[0004] In summary, 18 The difficulty in preparing F-DOPA has severely limited its clinical application. It is necessary to develop a novel F-DOPA with simple reaction, no transition metal involvement, high radiochemical yield and high specific activity. 18 The preparation method of F-DOPA is of great significance. Summary of the invention

[0005] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a 18 The invention relates to a preparation method of F-DOPA and its F-18 labeled precursor.

[0006] In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is: On the one hand, there is provided a 18 The F-18 labeled precursor of F-DOPA has a structural formula as shown in Formula I: Among them, R1 and R2 are hydroxyl protecting groups; R3 is a leaving group; R4 and R5 are independently hydrogen or amino protecting groups; and R6 is a carboxyl protecting group.

[0007] Further, R1 and R2 are independently methyl, allyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl, trifluoroacetyl, pivaloyl, benzoyl, p-toluenesulfonic acid acyl, methylsulfonyl, trifluoromethanesulfonyl, 2-tetrahydropyranyl, methoxymethyl, ethoxymethyl, 2-ethoxyethyl, benzyl, or R1 and R2 together form methylene, monofluoromethylene, difluoromethylene; R3 is leaving Group; R4, R5 are independently hydrogen or tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, benzyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, styryl, tert-butyl, dimethylformal amino protecting group; R6 is methyl, ethyl, tert-butyl, benzyl, phenyl.

[0008] Furthermore, R3 is , wherein R7, R8, R9, R10, and R11 are independently hydrogen, fluorine, chlorine, nitro, cyano, aldehyde, methoxyformyl, or carbamoyl electron-withdrawing groups; or R3 is benzoyl, acetyl, trifluoroacetyl, methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, , , , ; or R3 is , , , Pyridazine derivatives; or R3 is , , , , Pyridazinone derivatives; or R3 is , , , , Pyrimidine derivatives.

[0009] Further, its chemical structure is shown in any of the following: .

[0010] On the other hand, there is provided a 18 The preparation method of F-DOPA is based on 18 The F-18 labeled precursor of F-DOPA is labeled with F-18 by the following reaction. After the F-18 labeling reaction, the protecting group is removed and separated and purified to obtain 18 F-DOPA: .

[0011] Furthermore, the photocatalyst used for the photocatalytic labeling reaction includes 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate, 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine perchlorate, and riboflavin tetraacetate.

[0012] Furthermore, the light source is 385-500 nm blue light; the solvent is dichloromethane, dichloroethane, or acetonitrile.

[0013] The beneficial effects of the present invention are: The present invention provides a simple and efficient 18 The preparation method of F-DOPA is specifically to construct a key phenolic precursor compound and realize it through a simple and efficient photocatalytic deoxyfluorination reaction of aromatic hydrocarbons. 18 Preparation of F-DOPA. This method has few steps, high yield, simple operation, good reproducibility, and good automation production potential. Radioactive tracers synthesized using this method 18 F-DOPA has high specific activity, high chemical purity and high radioactivity purity.18 The clinical promotion of F-DOPA has important value. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 2; Figure 2 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 3; Figure 3 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 5; Figure 4 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 6; Figure 5 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 7; Figure 6 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 8; Figure 7 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 9; Figure 8 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 10; Fig. 9 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 14; Fig.10 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 16; Fig.11 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 22; Fig.12 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 26; Fig.13 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 43; Fig.14 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 58; Fig.15 This is the radio-HPLC spectrum of the F-18 labeled reaction solution of precursor 60. DETAILED DESCRIPTION

[0015] The specific implementation modes of the present invention are described below so that those skilled in the art can understand the present invention. However, it should be clear that the present invention is not limited to the scope of the specific implementation modes. For those of ordinary skill in the art, as long as various changes are within the spirit and scope of the present invention as defined and determined by the attached claims, these changes are obvious, and all inventions and creations utilizing the concept of the present invention are protected.

[0016] Example 1 Synthesis of Precursor 1 Synthesis of compound 1-a: 2-Hydroxy-4,5-dimethoxybenzaldehyde (2.72 g, 10 mmol, 1eq) and 1,8-diazacyclo[5,4,0]undecene-7 (1.85 g, 12 mmol, 1.2eq) were dissolved in dichloromethane (50 mL), stirred under ice bath for 20 minutes, (±)-BOC-A-phosphono glycine trimethyl ester (3.57 g, 12 mmol, 1.2eq) was added in batches, and then stirred at room temperature for 4 hours. TLC showed that (PE: EA = 2: 1) the raw materials were basically reacted. Saturated ammonium chloride water (20 mL) was added to quench the reaction, and the organic phase was washed with water and saturated sodium chloride in turn, dried over anhydrous sodium sulfate, filtered, concentrated to a small amount of solvent, added petroleum ether to slurry to obtain a white precipitate product, which was directly used in the next step. The raw material was dissolved in an appropriate amount of methanol, a catalytic amount of Pd / C (10%) was added, a hydrogen balloon was connected, the hydrogen was replaced three times, and the reaction was carried out at room temperature overnight. The product was filtered and concentrated to obtain a white solid product, and the obtained product was purified by chiral separation to obtain a white solid 1-b. 1 H NMR (400 MHz, Chloroform- d ) δ 6.83 (d, J =8.9 Hz, 1H), 6.71 (s, 1H), 6.46 (s, 1H), 5.14 (d, J = 8.2 Hz, 1H), 4.51 (q, J =7.2 Hz, 1H), 3.88 (s, 3H), 3.73 (d, J = 18.2 Hz, 6H), 2.96 (qd, J = 14.0, 6.4 Hz, 2H), 1.40 (s, 9H). Synthesis of precursor 1: Compound 1-b (355 mg, 1 mmol, 1.0 eq) and 4-chlorophenylboronic acid (234 mg, 1.5 mmol, 1.5 eq) were dissolved in 1,2-dichloroethane (100 mL), triethylamine (505 mg, 5 mmol, 5 eq) and copper acetate (218 mg, 1.2 mmol, 1.2 eq) were added, and then stirred at room temperature for 24 hours. 1 M citric acid aqueous solution (40 mL) was added, extracted with dichloromethane (50 mL × 3), the organic layers were combined, washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (PE: EA = 6: 1) to obtain 179.3 mg of white solid with a yield of 36.4%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.25 (d, J = 2.1 Hz, 2H), 6.83(d, J = 8.9 Hz, 2H), 6.71 (s, 1H), 6.46 (s, 1H), 5.15 (d, J = 8.2 Hz, 1H), 4.51(q, J = 7.1 Hz, 1H), 3.88 (s, 3H), 3.74 (d, J = 19.2 Hz, 6H), 2.96 (qd, J = 13.0,6.4 Hz, 2H), 1.40 (s, 9H). Synthesis of Precursor 2 Synthesis of Precursor 2: Compound 1-b (355 mg, 1 mmol, 1.0 eq) and 4-fluorobenzaldehyde (187 mg, 1.5 mmol, 1.5 eq) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (276 mg, 2 mmol, 2 eq) was added, and the mixture was reacted at room temperature overnight. Saturated sodium chloride was added for washing (100 mL), and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. The mixture was separated and purified by silica gel column chromatography (PE: EA = 6: 1) to obtain 281.3 mg of a white solid with a yield of 61.5%. 1 H NMR (400 MHz, Chloroform- d) δ 9.92 (s, 1H), 7.91 – 7.78 (m, 2H), 7.03 – 6.95 (m, 2H), 6.74 (s, 1H), 6.54 (s, 1H), 5.08 (d, J = 8.5 Hz,1H), 4.52 (d, J = 7.5 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.69 (s, 3H), 2.97(dd, J = 14.2, 5.7 Hz, 1H), 2.86 (dd, J = 13.9, 7.3 Hz, 1H), 1.40 (s, 9H). Precursor 3 was synthesized by changing the raw materials according to the synthesis method of precursor 1. White solid, yield 23.6%. 1 H NMR (400MHz, Chloroform- d ) δ 7.64 – 7.48 (m, 2H), 6.97 – 6.87 (m, 2H), 6.73 (s, 1H), 6.51 (s, 1H), 5.05 (d, J = 8.4 Hz, 1H), 4.51 (q, J = 7.2 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.70 (s, 3H), 2.95 (dd, J = 14.1, 5.7 Hz, 1H), 2.83 (dd, J = 14.1,7.4 Hz, 1H), 1.40 (s, 9H). Precursors 4, 5, 6, 7, 8, 9, 10, 11, and 12 were synthesized by replacing the raw materials according to the synthesis method of precursor 2.

[0017] Precursor 4, white solid, yield 53.6%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.84 – 7.72(m, 2H), 7.07 – 6.96 (m, 2H), 6.83 (s, 1H), 6.61 (s, 1H), 5.04 (d, J = 7.4 Hz,1H), 4.52 (q, J= 5.2 Hz, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 3.70 (s, 3H), 2.91(dd, J = 14.1, 5.7 Hz, 1H), 2.80 (dd, J = 12.1, 6.4 Hz, 1H), 1.40 (s, 9H). Precursor 5, white solid, yield 57.5%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.56 (d, J = 2.1Hz, 1H), 8.04 (dd, J = 8.9, 2.1 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J = 16.0 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 4.10 (td, J = 9.1, 5.2 Hz,1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.57 (s, 3H), 2.84 (dd, J = 13.9, 5.1 Hz, 1H),2.67 (dd, J = 13.9, 9.8 Hz, 1H), 1.30 (s, 9H). Precursor 6, white solid, yield 67.3%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.96 – 8.79(m, 1H), 8.44 – 8.20 (m, 1H), 6.99 (d, J = 9.3 Hz, 1H), 6.82 (s, 1H), 6.57 (s,1H), 5.16 (d, J = 8.6 Hz, 1H), 4.45 (d, J = 8.4 Hz, 1H), 3.96 – 3.58 (m, 9H), 3.00 (dd, J = 14.4, 5.5 Hz, 1H), 2.80 (dd, J = 14.2, 8.6 Hz, 1H), 1.37 (s, 9H).13 CNMR (100 MHz, Chloroform- d ) δ 172.08, 156.37, 155.07, 149.47, 147.64, 144.37,141.25, 138.83, 129.01, 122.23, 120.51, 117.36, 113.67, 104.62, 80.03, 77.37,77.05, 76.73, 60.40, 56.28, 53.96, 52.49, 32.69, 28.23, 22.62, 21.05, 19.44,14.20. Precursor 7, white solid, yield 68.9%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.73 (d, J =8.6 Hz, 1H), 7.40 – 7.20 (m, 2H), 6.75 (s, 1H), 6.50 (s, 1H), 5.03 (d, J = 8.2Hz, 1H), 4.49 (q, J = 7.3 Hz, 1H), 3.96 – 3.61 (m, 9H), 2.93 (dd, J = 14.1, 5.9Hz, 1H), 2.75 (dd, J = 14.0, 7.5 Hz, 1H), 1.39 (s, 9H). Precursor 8, white solid, yield 63.2%. 1 H NMR (400 MHz, DMSO- d 6) δ 8.39 (d, J = 10.5Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 6.99 (s, 1H), 6.81(s, 1H), 4.10 (td, J = 9.3, 4.9 Hz, 1H), 3.82 – 3.75 (m, 3H), 3.70 (s, 3H), 3.58 (s, 3H), 2.92 (dd, J = 14.1, 5.0 Hz, 1H), 2.68 (dd, J= 14.1, 10.1 Hz, 1H),1.29 (s, 9H). Precursor 9, white solid, yield 56.2%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.99 (d, J = 7.6Hz, 2H), 7.26 (d, J = 8.2 Hz, 1H), 6.95 (s, 1H), 6.43 (s, 1H), 4.30 – 4.16 (m,1H), 3.74 (s, 3H), 3.60 (d, J = 2.1 Hz, 6H), 3.13 (dd, J = 13.8, 5.6 Hz, 1H),2.85 (dd, J = 13.9, 9.7 Hz, 1H), 1.32 (s, 9H). 13 C NMR (100 MHz, DMSO- d 6) δ172.98, 155.75, 148.87, 148.77, 145.40, 118.77, 118.51, 117.92, 115.34,100.93, 78.70, 56.42, 56.38, 54.26, 52.26, 31.21, 28.54. Precursor 10, white solid, yield 63.1%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.29 (d, J = 8.3Hz, 1H), 6.96 (s, 1H), 6.67 (s, 1H), 4.25 (td, J = 9.1, 5.3 Hz, 1H), 3.75 (d, J =1.2 Hz, 3H), 3.68 – 3.60 (m, 6H), 3.11 (dd, J = 13.9, 5.4 Hz, 1H), 2.86 (dd, J =14.0, 10.1 Hz, 1H), 1.32 (s, 9H). Precursor 11, white solid, yield 49.3%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.28 (d,J = 8.4Hz, 1H), 6.97 (s, 1H), 6.68 (s, 1H), 4.25 (d, J = 7.2 Hz, 1H), 3.75 (s, 3H), 3.63 (d, J = 13.1 Hz, 6H), 3.10 (dd, J = 13.9, 5.3 Hz, 1H), 2.86 (dd, J = 14.0,10.2 Hz, 1H), 1.32 (s, 9H). Precursor 12, white solid, yield 68.2%. 1 H NMR (400 MHz, Chloroform- d ) δ 6.74 (s,1H), 6.42 (s, 1H), 5.09 (d, J = 8.4 Hz, 1H), 4.54 (q, J = 7.1 Hz, 1H), 3.89 (s,3H), 3.80 (s, 3H), 3.73 (s, 3H), 3.12 (dd, J = 14.3, 6.3 Hz, 1H), 3.03 (dd, J =14.3, 7.0 Hz, 1H), 1.39 (s, 9H). 13 C NMR (100 MHz, Chloroform- d ) δ 172.14,159.23, 154.97, 149.01, 147.63, 146.95, 119.04, 113.40, 107.32, 106.48,106.45, 102.35, 80.17, 77.36, 77.04, 76.73, 56.40, 56.36, 56.30, 56.26,53.64, 52.55, 52.51, 32.56, 28.22. Synthesis of Precursor 13 Synthesis of precursor 13: Compound 1-b (355 mg, 1 mmol, 1.0 eq) and methyl chloroformate (114 mg, 1.2 mmol, 1.2 eq) were dissolved in tetrahydrofuran (10 mL), triethylamine (202 mg, 2 mmol, 2 eq) was added, and the mixture was reacted at room temperature overnight. Saturated sodium chloride (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. The mixture was separated and purified by silica gel column chromatography (PE: EA = 6: 1) to obtain 282.1 mg of a white solid with a yield of 68.3%. 1 H NMR (400 MHz, Chloroform- d ) δ 6.67 (d, J = 6.1 Hz, 2H), 5.08 (d, J = 8.4Hz, 1H), 4.55 (q, J = 7.0 Hz, 1H), 3.91 (s, 3H), 3.85 (d, J = 4.8 Hz, 6H), 3.74(s, 3H), 2.98 (qd, J = 14.3, 6.4 Hz, 2H), 1.41 (s, 9H). Precursors 14, 15, 16, 17, 18, 19, 20, 21, and 22 are synthesized by following the synthesis method of precursor 13 by replacing the raw materials.

[0018] Precursor 14, white solid, yield 60.2%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.43 (dd, J = 8.7, 7.2 Hz, 2H), 7.35 – 7.28 (m, 3H), 6.79 (s, 1H), 6.68 (s, 1H), 5.10 (d, J = 8.4 Hz, 1H), 4.69 – 4.54 (m, 1H), 3.87 (d, J = 3.6 Hz, 6H), 3.75 (s, 3H), 3.08 (qd, J = 14.2, 6.3 Hz, 2H), 1.41 (s, 9H). Precursor 15, white solid, yield 51.4%. 1 H NMR (400 MHz, Chloroform- d) δ 8.37 –8.25 (m, 2H), 7.62 – 7.49 (m, 2H), 6.78 (s, 1H), 6.69 (s, 1H), 5.11 (d, J = 8.1Hz, 1H), 4.61 (q, J = 7.1 Hz, 1H), 3.87 (d, J = 2.5 Hz, 6H), 3.73 (s, 3H), 3.09(dt, J = 12.2, 6.2 Hz, 2H), 1.41 (s, 9H). Precursor 16, white solid, yield 56.1%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.47 (t, J =7.8 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 7.9 Hz, 2H), 6.70 (d, J = 6.6Hz, 2H), 5.09 (d, J = 8.2 Hz, 1H), 4.63 (q, J = 7.5, 6.9 Hz, 1H), 4.00 – 3.62 (m,9H), 3.04 (qd, J = 15.0, 14.4, 6.1 Hz, 2H), 1.41 (s, 9H). Precursor 17, white solid, yield 33.8%. 1 H NMR (400 MHz, Chloroform- d ) δ 6.75 (d, J =5.3 Hz, 2H), 5.05 (d, J = 8.5 Hz, 1H), 4.61 (d, J = 7.3 Hz, 1H), 3.88 (d, J = 6.8Hz, 6H), 3.75 (s, 3H), 3.19 (dd, J = 14.5, 5.7 Hz, 1H), 3.03 (dd, J = 14.6, 7.2Hz, 1H), 1.39 (s, 9H). Precursor 18, white solid, yield 39.7%. 1 H NMR (400 MHz, Chloroform- d ) δ 6.89 (s,1H), 6.68 (s, 1H), 5.12 (d, J = 8.2 Hz, 1H), 4.58 (d, J = 7.6 Hz, 1H), 3.87 (d, J =2.6 Hz, 6H), 3.72 (s, 3H), 3.25 (s, 3H), 3.10 (d, J = 5.9 Hz, 2H), 1.40 (s,9H). Precursor 19, white solid, yield 49.1%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.74 (d, J =8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 6.62 (s, 1H), 6.51 (s, 1H), 5.09 (d, J =8.4 Hz, 1H), 4.48 (q, J = 7.2 Hz, 1H), 3.84 (s, 3H), 3.72 (d, J = 1.3 Hz, 3H), 3.70 (s, 3H), 2.82 (qd, J = 14.5, 6.7 Hz, 2H), 2.46 (s, 3H), 1.38 (s, 9H). Precursor 20, white solid, yield 57.2%. 1 H NMR (400 MHz, Chloroform- d ) δ 6.66 (s,1H), 6.59 (s, 1H), 5.15 (d, J = 8.4 Hz, 1H), 4.54 (q, J = 7.2 Hz, 1H), 3.84 (d, J =4.8 Hz, 6H), 3.71 (s, 3H), 2.99 – 2.81 (m, 2H), 2.33 (s, 3H), 1.37 (s, 9H). Precursor 22, white solid, yield 55.1%.1 H NMR (400 MHz, Chloroform- d ) δ 8.35 –8.08 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 6.73 (d, J = 4.2Hz, 2H), 5.13 (d, J = 8.7 Hz, 1H), 4.58 (q, J = 8.1, 7.6 Hz, 1H), 3.87 (d, J = 10.6Hz, 6H), 3.64 (s, 3H), 2.96 – 2.75(m, 2H), 1.39 (s, 9H). Synthesis of Precursor 23 Synthesis of compound 23-a: 2-Fluoro-4,5-dimethoxybenzaldehyde (9.2 g, 50 mmol, 1.0 eq) and 4-chlorophenol (6.43 g, 55 mmol, 1.1 eq) were dissolved in N,N-dimethylformamide (200 mL), cesium carbonate (24.5 g, 75 mmol, 1.5 eq) was added, and the mixture was reacted at 110 °C for 24 hours. Saturated sodium chloride was added for washing (200 mL), and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. The mixture was separated and purified by silica gel column chromatography (PE: EA = 5: 1) to obtain 6.69 g of a white solid with a yield of 48.1%. 1 H NMR (400 MHz, Chloroform- d ) δ 10.18(s, 1H), 7.32 (s, 1H), 7.27 – 7.21 (m, 2H), 6.94 – 6.83 (m, 2H), 6.40 (s,1H), 6.29 – 6.19 (m, 1H), 3.88 (s, 3H). Synthesis of compound 23-b: 23-a (2.79 g, 10 mmol, 1.0 eq) and potassium carbonate (2.1 g, 15 mmol, 1.5 eq) were dissolved in acetonitrile (100 mL), and benzyl bromide (1.88 g, 11 mmol, 1.1 eq) was added dropwise, and the mixture was reacted at room temperature overnight. Saturated sodium chloride was added for washing (200 mL), and the mixture was extracted with dichloromethane (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The white solid product (3.4 g) was obtained by slurrying with petroleum ether and dichloromethane, with a yield of 93.1%. 1 H NMR (400MHz, Chloroform- d ) δ 10.23 (d, J = 1.4 Hz, 1H), 7.40 – 7.23 (m, 8H), 6.86 –6.77 (m, 2H), 6.40 (d, J = 1.3 Hz, 1H), 5.09 (s, 2H), 3.93 (d, J = 1.4 Hz, 3H). Synthesis of compound 23-d: 23-b (3.68 g, 10 mmol, 1eq) and 1,8-diazacyclo[5,4,0]undecene-7 (1.85 g, 12 mmol, 1.2eq) were dissolved in dichloromethane (50 mL), stirred under ice bath for 20 minutes, (±)-BOC-A-phosphono glycine trimethyl ester (3.57 g, 12 mmol, 1.2eq) was added in batches, and then stirred at room temperature for 4 hours. TLC showed that (PE: EA = 2: 1) the raw materials were basically reacted. Saturated ammonium chloride water (20 mL) was added to quench the reaction, and the organic phase was washed with water and saturated sodium chloride in turn, dried over anhydrous sodium sulfate, filtered, concentrated to a small amount of solvent, and added with petroleum ether to slurry to obtain a white precipitate product, which was directly used in the next step. The raw material was dissolved in an appropriate amount of methanol, a catalytic amount of Pd / C (10%) was added, a hydrogen balloon was connected, the hydrogen was replaced three times, and the reaction was allowed to proceed overnight at room temperature. The residue was filtered and concentrated to obtain a white solid product, which was purified by chiral separation to obtain a white solid 23-d. 1 H NMR (400 MHz, Chloroform- d ) δ 7.33 – 7.27 (m, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.97 – 6.89 (m, 2H), 6.70 (s, 1H), 6.49 (s, 1H), 5.63 (s,1H), 5.26 (d, J= 8.0 Hz, 1H), 4.50 (d, J = 7.6 Hz, 1H), 3.88 (s, 3H), 3.69 (s,3H), 3.00 (d, J = 6.4 Hz, 2H), 1.40 (s, 9H). Synthesis of precursor 23: Compound 23-d (256 mg, 0.5 mmol, 1 eq) and p-toluenesulfonyl chloride (114 mg, 6 mmol, 1.2 eq) were dissolved in tetrahydrofuran (10 mL), triethylamine (101 mg, 1 mmol, 2 eq) was added, and the mixture was reacted at room temperature overnight. Saturated sodium chloride (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. The mixture was separated and purified by silica gel column chromatography (PE: EA = 6: 1) to obtain 118.1 mg of a white solid with a yield of 39.4%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.70 (d, J = 8.3 Hz, 2H), 7.35 – 7.28(m, 2H), 7.24 (s, 1H), 7.15 – 7.05 (m, 2H), 6.93 – 6.84 (m, 2H), 6.73 (s,1H), 6.63 (s, 1H), 5.19 (d, J = 8.3 Hz, 1H), 4.60 – 4.47 (m, 1H), 3.67 (s, 3H), 3.59 (s, 3H), 3.12 – 2.96 (m, 2H), 2.41 (s, 3H), 1.39 (s, 9H). Synthesis of Precursor 32: Synthesis of 32-a: Synthesis of compound 32-a: 2-Fluoro-4,5-dimethoxybenzaldehyde (9.2 g, 50 mmol, 1.0 eq) and 4-hydroxy-N,N-dimethylbenzamide (9.1 g, 55 mmol, 1.1 eq) were dissolved in N,N-dimethylformamide (200 mL), potassium carbonate (10.4 g, 75 mmol, 1.5 eq) was added, and the mixture was reacted at 100 °C for 24 hours. Saturated sodium chloride was added for washing (200 mL), and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. The mixture was separated and purified by silica gel column chromatography (PE: EA = 5: 1) to obtain 6.47 g of a white solid with a yield of 41.6%. 1 H NMR (400 MHz, Chloroform- d ) δ 10.22 (d, J = 1.4 Hz, 1H), 7.48 – 7.43 (m, 2H), 7.40(d, J = 1.4 Hz, 1H), 7.05 – 6.97 (m, 2H), 6.50 (s, 1H), 3.94 (d, J = 1.3 Hz, 3H),3.85 (d, J = 1.2 Hz, 3H), 3.12 – 3.03 (m, 6H). Synthesis of compound 32-c: 32-a (3.159 g, 10 mmol, 1.0 eq) was dissolved in dichloromethane (100 mL), and boron tribromide (7.5 g, 30 mmol, 3 eq) was added dropwise at 0°C, and the mixture was reacted in an ice bath for 4 hours. Ice methanol was added to quench the reaction, and the solvent was removed by concentration under reduced pressure. 100 mL of ethyl acetate was added to dissolve the residue, and the mixture was concentrated under reduced pressure. 1.9 g of brown solid product was obtained by slurrying with petroleum ether and dichloromethane, which was directly used in the next step. Compound 32-b (3.01 g, 10 mmol, 1 eq) and Boc anhydride (6.54 g, 30 mmol, 3 eq) were dissolved in tetrahydrofuran (100 mL), and triethylamine (4.05 g, 40 mmol, 4 eq) and 4-dimethylaminopyridine (122 mg, 1 mmol, 0.1 eq) were added to react at room temperature overnight. Saturated sodium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was separated and purified by silica gel column chromatography (PE: EA = 8: 1) to obtain a white solid. 1 H NMR (400 MHz, Chloroform- d) δ 10.38(d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.9 Hz, 1H), 7.49 (dd, J = 8.5, 2.1 Hz, 2H), 7.15– 7.08 (m, 2H), 6.89 (d, J = 1.9 Hz, 1H), 3.07 (s, 6H), 1.54 (dd, J = 13.7, 2.4Hz, 18H). Synthesis of precursor 32: 32-c (0.51 g, 1 mmol, 1 eq) and 1,8-diazacyclo[5,4,0]undecene-7 (0.185 g, 1.2 mmol, 1.2 eq) were dissolved in dichloromethane (50 mL), stirred under ice bath for 20 minutes, (±)-BOC-A-phosphonoglycine trimethyl ester (0.357 g, 1.2 mmol, 1.2 eq) was added in batches, and then stirred at room temperature for 4 hours. TLC showed that (PE: EA = 2: 1) the raw materials were basically reacted. Saturated ammonium chloride water (20 mL) was added to quench the reaction, and the organic phase was washed with water and saturated sodium chloride in turn, dried over anhydrous sodium sulfate, filtered, concentrated to a small amount of solvent, and added to petroleum ether to slurry to obtain a white precipitate product, which was directly used in the next step. The raw material was dissolved in an appropriate amount of methanol, a catalytic amount of Pd / C (10%) was added, a hydrogen balloon was connected, the hydrogen was replaced three times, and the reaction was allowed to proceed overnight at room temperature. The residue was filtered and concentrated to obtain a white solid product, which was purified by chiral separation to obtain a white solid. 1 H NMR (400 MHz, Chloroform- d ) δ 7.47 – 7.40 (m, 2H), 7.14 (s,1H), 7.07 – 7.00 (m, 2H), 6.77 (s, 1H), 5.18 (d, J = 8.2 Hz, 1H), 4.57 (d, J =7.2 Hz, 1H), 3.67 (s, 3H), 3.07 (s, 8H), 1.45 (d, J = 46.6 Hz, 27H). Precursor 30 is synthesized by changing the raw materials according to the synthesis method of precursor 32. White solid, 1 H NMR (400 MHz, Chloroform- d) δ 8.08 – 8.01 (m, 2H), 8.00 – 7.94 (m, 2H), 7.58 – 7.46 (m,2H), 7.42 – 7.30 (m, 6H), 7.25 (s, 1H), 7.18 – 7.06 (m, 3H), 6.82 (s, 1H),5.32 (s, 1H), 4.64 (d, J = 7.5 Hz, 1H), 3.71 (s, 3H), 3.20 (d, J = 6.7 Hz, 2H) ,1.39 (s, 9H). Precursor 33 was synthesized by changing the raw materials according to the synthesis method of precursor 32. White solid, 1 H NMR (400 MHz, Chloroform- d ) δ 7.35 (dd, J = 8.5, 7.3 Hz, 2H), 7.19 – 7.08 (m, 2H), 7.08 –6.97 (m, 2H), 6.69 (s, 1H), 5.23 (d, J = 8.1 Hz, 1H), 4.57 (q, J = 7.1 Hz, 1H),3.67 (s, 3H), 3.12 (t, J = 5.8 Hz, 2H), 1.50 (s, 18H), 1.39 (s, 9H). Precursor 34 was synthesized by changing the raw materials according to the synthesis method of precursor 32. White solid, 1 H NMR (400 MHz, Chloroform- d ) δ 7.19 – 7.08 (m, 3H), 7.00 – 6.89 (m, 2H), 6.64 (s, 1H), 5.25(d, J = 8.1 Hz, 1H), 4.63 – 4.49 (m, 1H), 3.67 (s, 3H), 3.13 (d, J = 6.5 Hz, 2H),1.52 (d, J = 17.4 Hz, 18H), 1.42 – 1.36 (m, 9H). Synthesis of Precursor 43 Synthesis of compound 43-a: (S)-(2-((tert-butyloxycarbonyl)amino)-3-(3,4-dihydroxyphenyl)propionic acid methyl ester (3.11 g, 10 mmol, 1eq) and chloromethyl ether (2.85 g, 30 mmol, 3eq) were dissolved in tetrahydrofuran (100 ml), and (3.88 g, 30 mmol, 3eq) was added. The mixture was reacted at 40°C for 24 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and then methyl tert-butyl ether (180 mL) and water (120 mL) were added in sequence. The organic layer was washed with distilled water (2 x 100 mL), 5% acetic acid aqueous solution (2 x 100 mL), 10% potassium carbonate aqueous solution (2 x 100 mL) and saturated brine (3 x 100 mL) in sequence. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain 3.61 g of a yellow oil with a yield of 84.3%.

[0019] Synthesis of compound 43-b: Compound 43-a (2.14 g, 5 mmol, 1 eq), potassium carbonate (2.08 g, 15 mmol, 3 eq), and iodine (1.79 g, 7 mmol, 1.4 eq) were dissolved in dichloromethane (100 ml) and stirred at room temperature for 10 minutes. A dichloromethane solution (50 ml) of [bis(trifluoroacetyloxy)iodo]benzene (3.23 g, 7.5 mmol, 1.5 eq) was added dropwise under nitrogen protection. The reaction mixture was reacted at room temperature for 3 hours, and the reaction mixture was washed with 10% potassium carbonate aqueous solution (2 x 100 mL), 5% sodium sulfite aqueous solution (2 x 100 mL) and water (150 ml) in sequence. The organic phase was dried over magnesium sulfate, filtered and concentrated. Column chromatography purification (PE: EA = 5: 1) gave 1.38 g of a light yellow solid with a yield of 49.7%. 1 H NMR (400 MHz, Chloroform- d )7.54 (s, 1H), 6.97 (s, 1H), 5.19 (s, 4H), 5.03 (d, J = 8.4 Hz, 1H), 4.58 (m,1H), 3.70 (m, 7H), 3.19 (dd, J = 14.0, 5.7 Hz, 1H), 2.99 (dd, J = 14.0, 7.9 Hz,1H),1.24 (t, J = 7.1 Hz, 3H), 1.35 (s, 9H), 1.23 (t, J = 7.1 Hz, 3H). Synthesis of compound 43-c: Compound 43-b (1.107 g, 2 mmol, 1eq), potassium acetate (0.39 g, 4mmol, 2eq), diboron pinacol ester (1.02 g, 4 mmol, 2eq) and Pd(dppf)2Cl2 (0.165 g, 0.2 mmol, 0.1eq) were dissolved in dimethyl sulfoxide (100 ml) and reacted overnight under nitrogen protection. The reaction mixture was cooled to room temperature, and then ethyl acetate (200 mL) and water (150 mL) were added in sequence, and the organic layer was washed with saturated brine (4 x 100 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was dissolved in methanol (20 ml), and hydrogen peroxide (33%, 10 ml) was added, and the reaction was carried out at room temperature for 1 hour. Ethyl acetate (200 mL) and water (150 mL) were added, and the organic layer was washed with saturated brine (4 x 100 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated, and purified by column chromatography (PE: EA = 5: 1) to obtain 0.45 g of a light yellow solid product.

[0020] 1 H NMR (400 MHz, Chloroform- d ) 7.94 (s, 1H), 7.07 (s, 1H), 6.43 (s,1H), 5.1,7 (s, 4H), 4.97 (d, J = 8.8 Hz, 1H), 4.59 (m, 1H), 3.70 (m, 7H), 3.17(dd, J = 14.3, 5.7 Hz, 1H), 2.97 (dd, J = 12.9, 7.3 Hz,1H),1.24 (t, J = 6.6 Hz, 3H), 1.36 (s, 9H), 1.23 (t, J = 7.5 Hz, 3H). Precursor 43 was synthesized by changing the raw materials according to the synthesis method of precursor 2. White solid, yield: 51.6%. 1 H NMR (400MHz, Chloroform- d ) δ 7.73 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 11.2 Hz, 2H), 7.08(s, 1H), 6.84 (s, 1H), 5.31 – 5.25 (m, 2H), 5.22 (s, 2H), 5.05 (d, J= 8.6 Hz,1H), 4.49 (q, J = 7.2 Hz, 1H), 3.80 (q, J = 7.1 Hz, 2H), 3.73 (d, J = 8.1 Hz, 5H),2.97 (dd, J = 13.9, 5.7 Hz, 1H), 2.77 (dd, J = 13.9, 7.2 Hz, 1H), 1.39 (s, 9H), 1.30 – 1.26 (m, 3H), 1.19 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ172.08, 161.63, 154.95, 147.54, 145.96, 145.52, 135.43, 121.64, 121.07,120.96, 119.32, 117.66, 115.37, 114.95, 109.28, 108.87, 94.41, 93.93, 80.03,77.40, 77.08, 76.76, 64.65, 64.62, 64.58, 53.63, 52.43, 52.40, 41.32, 32.81,29.67, 29.04, 28.23, 22.60, 21.02, 20.42, 19.42, 15.11, 15.08, 14.18, 11.41. Precursor 44 was synthesized by changing the raw materials according to the synthesis method of precursor 2. White solid, yield: 62.9%. 1 H NMR (400MHz, Chloroform- d ) δ 7.61 (d, J = 9.5 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.11 (s,1H), 6.84 (s, 1H), 5.31 – 5.28 (m, 2H), 5.23 (s, 2H), 5.07 (d, J = 8.6 Hz, 1H),4.48 (q, J = 7.8, 7.3 Hz, 1H), 3.81 (q, J = 7.1 Hz, 2H), 3.74 (d, J= 5.3 Hz, 5H),3.02 (dd, J = 14.0, 5.4 Hz, 1H), 2.80 (dd, J = 14.0, 7.4 Hz, 1H), 1.27 (t, J = 7.0Hz, 5H), 1.20 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, Chloroform- d ) δ 172.00,155.49, 154.98, 152.88, 150.60, 150.49, 147.56, 145.68, 145.47, 122.23,122.01, 121.69, 121.42, 119.34, 114.39, 114.34, 113.20, 113.15, 110.02,109.94, 108.55, 94.39, 93.88, 80.08, 77.38, 77.06, 76.75, 64.66, 53.61,52.46, 41.33, 36.06, 33.70, 32.68, 29.68, 29.04, 28.88, 28.18, 27.65, 26.90,25.81, 22.60, 20.43, 19.42, 18.75, 15.12, 15.09, 14.30, 11.41. Synthesis of Precursor 55 Synthesis of precursor 55: 2-(tert-butyl)-4,5-dichloropyridazin-3(2H)-one (199 mg, 0.90 mmol), 55-a (150 mg, 0.45 mmol) and cesium carbonate (440 mg, 1.35 mmol) were dissolved in N,N-dimethylformamide (10 ml), reacted at 70°C for 4 hours, and monitored by TLC spot plate (PE:EA=2:1). After the reaction was completed, water (100 ml) was added to the reaction solution, extracted with ethyl acetate (3 x 100 mL), and the organic phase was washed with saturated brine. After concentration under reduced pressure, the product was purified by silica gel column chromatography to obtain 86 mg of light yellow solid, with a yield of 35.4%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.33 (s,1H), 6.75 (s, 1H), 6.51 (s, 1H), 5.18 (d, J= 8.4 Hz, 1H), 4.51 (q, J = 7.6 Hz,1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.71 (s, 3H), 3.02 (dd, J = 14.1, 5.4 Hz, 1H), 2.92 – 2.84 (m, 1H), 1.64 (s, 9H), 1.38 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 172.14, 158.86, 155.08, 153.07, 149.19, 147.18, 144.93, 126.04, 119.82,113.53, 104.31, 80.02, 66.64, 56.34, 56.28, 53.99, 52.53, 32.43, 28.26,27.83. Precursors 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, and 68 are synthesized by following the synthesis method of precursor 55 by replacing the raw materials.

[0021] Precursor 56: pale yellow solid, yield: 32.5%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.58(dd, J = 7.6, 2.0 Hz, 3H), 7.46 (dd, J = 8.5, 6.7 Hz, 2H), 7.42 – 7.37 (m, 1H), 6.78 (s, 1H), 6.56 (s, 1H), 5.19 (d, J = 8.5 Hz, 1H), 4.55 (q, J = 7.5 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 3.10 (dd, J = 14.1, 5.4 Hz, 1H), 2.90(dd, J = 14.1, 8.0 Hz, 1H), 1.37 (s, 9H). 13 C NMR (101 MHz, Chloroform- d) δ172.12, 155.05, 153.34, 149.28, 147.31, 144.82, 141.18, 129.19, 128.83,128.57, 125.27, 119.82, 113.68, 104.13, 80.10, 56.38, 56.28, 53.95, 52.58,32.67, 28.26. Precursor 57: yellow solid, yield: 48.1%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.56 (s,1H), 7.37 (d, J = 1.8 Hz, 1H), 7.36 – 7.33 (m, 2H), 7.21 (t, J = 4.0 Hz, 1H), 6.78 (s, 1H), 6.56 (s, 1H), 5.19 (d, J = 8.5 Hz, 1H), 4.55 (q, J = 8.1, 7.7 Hz,1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 3.10 (dd, J = 14.1, 5.4 Hz, 1H),2.90 (dd, J = 14.1, 8.0 Hz, 1H), 2.40 (s, 3H), 1.38 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 172.13, 158.23, 155.05, 153.32, 149.27, 147.28, 144.84,141.10, 138.91, 129.42, 129.05, 128.68, 125.90, 122.39, 119.80, 113.68,104.11, 80.10, 56.37, 56.28, 53.95, 52.57, 32.67, 28.26, 21.37. Precursor 58: pale yellow solid, yield: 49.6%. 1 H NMR (400 MHz, Chloroform- d) δ 7.47 –7.43 (m, 2H), 7.40 (s, 1H), 7.35 – 7.28 (m, 3H), 6.75 (s, 1H), 6.48 (s, 1H),5.32 (s, 2H), 5.16 (d, J = 8.5 Hz, 1H), 4.55 – 4.44 (m, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 3.69 (s, 3H), 3.02 (dd, J = 14.1, 5.4 Hz, 1H), 2.84 (dd, J = 14.1, 8.0Hz, 1H), 1.36 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 172.08, 155.03,153.57, 149.21, 147.24, 144.80, 135.53, 129.25, 128.66, 128.52, 128.27,119.80, 113.59, 104.18, 80.04, 56.33, 56.27, 56.10, 53.92, 52.52, 32.55,28.25. Precursor 59: white solid, yield: 24.6%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.49 (d, J = 9.1 Hz, 1H), 7.19 (d, J = 9.1 Hz, 1H), 6.70 (s, 1H), 6.64 (s, 1H), 5.12 (d, J =8.3 Hz, 1H), 4.52 (q, J = 7.2 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.69 (s,3H), 2.97 (dd, J = 14.2, 6.1 Hz, 1H), 2.86 (dd, J = 14.2, 7.1 Hz, 1H), 1.38 (s,9H). 13 C NMR (101 MHz, Chloroform- d) δ 172.49, 165.03, 155.11, 152.16, 148.93,146.96, 144.85, 131.59, 119.77, 119.67, 113.16, 105.66, 79.92, 56.22, 56.07,53.75, 52.38, 32.82, 28.29. Precursor 60: white solid, yield: 27.2%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.42 (s,1H), 6.78 (s, 1H), 6.50 (s, 1H), 5.18 (d, J = 8.5 Hz, 1H), 4.52 (q, J = 7.7, 5.3Hz, 1H), 3.91 (s, 3H), 3.83 (d, J = 2.0 Hz, 6H), 3.74 (s, 3H), 3.07 (dd, J =14.1, 5.3 Hz, 1H), 2.88 (dd, J = 14.1, 8.1 Hz, 1H), 1.39 (s, 9H). 13 C NMR (101MHz, Chloroform- d ) δ 172.12, 158.76, 155.05, 153.79, 149.22, 147.18, 144.94,128.30, 119.72, 113.65, 103.99, 80.07, 56.30, 56.27, 53.93, 52.54, 40.84,32.56, 28.24. Precursor 61: white solid, yield: 82.0%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.43 (d, J = 5.7 Hz, 1H), 6.78 (d, J = 5.6 Hz, 1H), 6.71 (s, 1H), 6.59 (s, 1H), 5.03 (d, J =8.5 Hz, 1H), 4.52 (q, J= 7.2 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.71 (s,3H), 2.96 (dd, J = 14.2, 5.9 Hz, 1H), 2.82 (dd, J = 14.3, 7.2 Hz, 1H), 1.38 (s,9H). 13 C NMR (101 MHz, Chloroform- d ) δ 172.31, 165.91, 163.05, 155.09, 148.94,147.36, 143.88, 119.64, 114.27, 112.88, 105.57, 104.33, 56.12, 53.60, 52.55,32.07, 28.32. Precursor 62: white solid, yield: 29.3%. 1 H NMR (400 MHz, Chloroform- d ) δ 6.76 (s,1H), 5.94 (s, 1H), 5.20 (d, J = 8.3 Hz, 1H), 4.60 (td, J = 8.1, 5.3 Hz, 1H), 3.87(s, 3H), 3.74 (s, 3H), 3.70 (s, 3H), 3.22 (dd, J = 14.2, 5.5 Hz, 1H), 3.12 (dd, J = 14.2, 8.1 Hz, 1H), 1.38 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 172.45,155.99, 155.15, 151.31, 149.49, 148.92, 146.75, 146.22, 130.84, 117.23,114.13, 99.25, 80.02, 56.47, 56.34, 54.04, 52.43, 32.15, 28.28. Precursor 63: white solid, yield: 57.6%. 1 H NMR (400 MHz, Chloroform- d) δ 8.82 (s,2H), 6.73 (s, 1H), 6.58 (s, 1H), 5.13 (d, J = 8.3 Hz, 1H), 4.49 (q, J = 6.8 Hz,1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.74 (s, 3H), 2.97 (dd, J = 14.3, 5.8 Hz, 1H),2.86 (dd, J = 14.4, 6.8 Hz, 1H), 1.39 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ172.32, 170.47, 160.84, 160.42, 155.07, 148.85, 147.22, 143.62, 119.77,113.07, 106.36, 105.60, 80.03, 56.16, 53.62, 52.46, 32.52, 28.28. Precursor 64: white solid, yield: 67.9%. 1 H NMR (400 MHz, Chloroform- d ) δ 6.71 (s,1H), 6.62 (s, 1H), 5.03 (d, J = 8.5 Hz, 1H), 4.54 (q, J = 6.9 Hz, 1H), 3.89 (s,3H), 3.84 (s, 3H), 3.71 (s, 3H), 2.97 (dd, J = 14.3, 6.0 Hz, 1H), 2.88 (dd, J =14.3, 6.5 Hz, 1H), 1.38 (s, 9H). 19 F NMR (377 MHz, Chloroform- d ) δ -149.12. 13 CNMR (101 MHz, Chloroform- d) δ 172.22, 155.00, 148.73, 147.47, 143.10, 119.72,112.94, 105.56, 80.13, 56.18, 56.15, 53.62, 52.45, 32.67, 28.24. Precursor 65: white solid, yield: 42.7%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.35 (d, J = 2.0 Hz, 1H), 6.72 (s, 1H), 6.64 (s, 1H), 5.05 (d, J = 8.4 Hz, 1H), 4.55 (q, J =7.0 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.70 (s, 3H), 2.98 (dd, J = 14.3, 6.0Hz, 1H), 2.88 (dd, J = 14.3, 6.7 Hz, 1H), 1.38 (s, 9H). 19 F NMR (377 MHz, Chloroform- d ) δ -154.26. 13 C NMR (101 MHz, Chloroform- d ) δ 172.30, 156.91 (d, J =369.5 Hz), 153.62, 148.69, 147.35, 145.81, 145.79 (d, J = 266.0 Hz), 145.61,143.01, 119.76, 112.91, 105.69, 80.03, 56.17, 56.15, 53.53 (d, J = 19.0 Hz),52.42, 32.51, 28.25. Precursor 66: white solid, yield: 61.9%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.47 (s,1H), 6.73 (s, 1H), 6.65 (s, 1H), 5.09 (d, J = 8.5 Hz, 1H), 4.55 (q,J = 7.5 Hz,1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.69 (s, 3H), 2.96 (dd, J = 14.3, 5.7 Hz, 1H),2.84 (dd, J = 14.3, 7.7 Hz, 1H), 1.37 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ172.38, 165.05, 158.23, 155.14, 148.61, 147.37, 143.28, 119.74, 116.95,112.69, 105.78, 80.01, 56.15, 53.85, 53.44, 52.40, 32.53, 28.25. Precursor 67: white solid, yield: 39.4%. 1 H NMR (400 MHz, Chloroform- d ) δ 6.80 (s,1H), 6.69 (s, 1H), 6.55 (s, 1H), 5.11 (d, J = 8.5 Hz, 1H), 4.47 (q, J = 8.0, 7.5Hz, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.70 (s, 3H), 2.94 (dd, J = 14.2, 5.4 Hz,1H), 2.73 (dd, J = 14.2, 8.1 Hz, 1H), 1.37 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.94, 156.16, 155.35, 154.98, 149.53, 147.93, 147.84, 143.20, 120.18,113.75, 112.28, 104.25, 80.19, 56.37, 56.27, 53.80, 52.58, 32.84, 28.22. Precursor 68: yellow solid, yield: 34.2%. 1 H NMR (400 MHz, Chloroform- d) δ 7.77 (s,1H), 6.74 (s, 1H), 6.69 (s, 1H), 5.09 (d, J = 8.3 Hz, 1H), 4.55 – 4.34 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.68 (s, 3H), 2.94 (d, J = 6.8 Hz, 2H), 1.37 (s,9H). 13 C NMR (101 MHz, Chloroform- d ) δ 172.38, 162.02, 154.95, 151.52, 148.90,147.50, 143.83, 133.61, 119.89, 112.98, 111.30, 106.31, 105.50, 56.21, 56.12,53.76, 52.48, 33.04, 28.25. Example 2 18 F-18 Labeling of F-DOPA Precursor Compounds 18 Preparation of F-DOPA: 18 Synthesis of F-DOPA: Take 0.01 mmol of precursor, 2 mg of 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate (CAS NO.1810004-87-5) in a V-shaped reaction bottle, add 0.5 ml of dichloromethane or dichloroethane, and add the pretreated 18 F - Solution, 456 nm LED light for 15 minutes to generate important labeled intermediates 18 FI. After removing the reaction solvent, the intermediate 18 FI can be prepared by removing the protective group by concentrated hydrochloric acid, concentrated sulfuric acid or hydrogen iodide with or without heating, and then adjusting the pH of the reaction solution to 6-7 and purifying by HPLC. 18 The F-18 labeled chemical conversion rate of the precursor was detected by radioactive HPLC and the results are shown in the following table. (ND: not detected). HPLC conditions: 70% MeCN: 30% KK (potassium phosphate buffer, pH: 8.0), flow rate: 1ml / min,.

[0022] Precursor Radiochemical conversion rate (RCC) Precursor 18F-Chemical conversion rate 1 ND 23 5.2% 2 4.7% 26 45.7% 3 11% 33 27.3% 4 10% 34 6.4% 5 39% 43 34.8% 6 75% 44 8.4% 7 83% 55 29.8% 8 70.5% 56 35.6% 9 14% 57 41.5% 10 22% 58 49.6% 11 19% 59 14.1% 12 ND 60 66.1% 13 37% 61 ND 14 77% 62 7.4% 15 ND 63 6.3% 16 41.5% 64 0.8% 17 16.5% 65 ND 18 4.9% 66 4.1% 19 12.5% 67 35.7% 22 13% 68 7.4% In summary, the present invention provides a simple and efficient 18The preparation method of F-DOPA is specifically to construct a key phenolic precursor compound and realize it through a simple and efficient photocatalytic deoxyfluorination reaction of aromatic hydrocarbons. 18 Preparation of F-DOPA. This method has few steps, high yield, simple operation, good reproducibility, and good automation production potential. Radioactive tracers synthesized using this method 18 F-DOPA has high specific activity, high chemical purity and high radioactivity purity. 18 The clinical promotion of F-DOPA has important value.

[0023] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

Claims

1. A 18 The F-18 labeled precursor of F-DOPA is characterized by: The structural formula of the F-18 labeled phenolic precursor compound is shown in Formula I: Among them, R1 and R2 are hydroxyl protecting groups; R3 is a leaving group; R4 and R5 are independently hydrogen or amino protecting groups; and R6 is a carboxyl protecting group.

2. according to claim 1 18 The F-18 labeled precursor of F-DOPA is characterized by: R1, R2 are independently methyl, allyl, tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl, trifluoroacetyl, pivaloyl, benzoyl, p-toluenesulfonic acid acyl, methylsulfonyl, trifluoromethylsulfonyl, 2-tetrahydropyranyl, methoxymethyl, ethoxymethyl, 2-ethoxyethyl, benzyl, or R1 and R2 together form methylene, monofluoromethylene, difluoromethylene; R3 is a leaving group; R4, R5 are independently hydrogen or tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, benzyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, styryl, tert-butyl, dimethylformal amino protecting group; R6 is methyl, ethyl, tert-butyl, benzyl, phenyl.

3. According to claim 1 18 The F-18 labeled precursor of F-DOPA is characterized by: R3 is , wherein R7, R8, R9, R10, and R11 are independently hydrogen, fluorine, chlorine, nitro, cyano, aldehyde, methoxyformyl, or carbamoyl electron-withdrawing groups; or R3 is benzoyl, acetyl, trifluoroacetyl, methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, , , , ; or R3 is , , , Pyridazine derivatives; or R3 is , , , , Pyridazinone derivatives; or R3 is , , , , Pyrimidine derivatives.

4. according to claim 1 18 The F-18 labeled precursor of F-DOPA is characterized by: Its chemical structure is shown as any one of the following: 。 5. A 18 The preparation method of F-DOPA is characterized in that: Adopt any one of claims 1-4 18 The F-18 labeled precursor of F-DOPA is labeled with F-18 by the following reaction. After the F-18 labeling reaction, the protecting group is removed and separated and purified to obtain 18 F-DOPA: 。 6. According to claim 5 18 The preparation method of F-DOPA is characterized in that: The photocatalysts used for the photocatalytic labeling reaction include 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate, 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine perchlorate, and riboflavin tetraacetate.

7. According to claim 5 18 The preparation method of F-DOPA is characterized in that: The light source is 385-500 nm blue light; the solvents are dichloromethane, dichloroethane, and acetonitrile.

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