A 18 Process for the preparation of F-DOPA and F-18 labeled precursors thereof

Abstract

This invention relates to the field of biomedical technology, specifically to a... 18 A method for preparing F-DOPA and its F-18 labeled precursor. The structural formula of the F-18 labeled phenolic precursor compound is shown in Formula I: ; wherein 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. This invention provides a simple and efficient method for preparing F-DOPA. 18 The preparation method of F-DOPA involves constructing key phenolic precursor compounds and then achieving 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 potential for automated production. Radioactive tracers synthesized using this method. 18 F-DOPA has high specific activity, high chemical purity, and high radioactive purity, and is effective against... 18 The clinical promotion of F-DOPA is of great value.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to a... 18 Preparation method of F-DOPA and its F-18 labeled precursor. Background Technology

[0002] 6-[18F]Fluoro-L-DOPA ( 18 F-DOPA is an analogue of L-DOPA (L-DOAP). Its metabolic process in the body is similar to that of L-DOPA, and it can reflect the anabolic metabolism of L-DOPA in the body. 18 F-DOPA is a positron emission tomography (PET) imaging agent used to study dopamine function in the brain, and it has been widely used clinically in the diagnosis of neurological diseases such as schizophrenia, Parkinson's disease, and Alzheimer's disease. In recent years, 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, neuroblastomas, medullary thyroid carcinomas, pheochromocytomas, paragangliomas, and malignant tumors of the central nervous system.

[0003] In the existing technology, 18 F-DOPA can be synthesized through electrophilic F-18 substitution and nucleophilic F-18 substitution. However, 18 F-DOPA's electrophilic F-18 marking method requires the use of highly corrosive gases. 18 The apparatus for preparing F]F2, the resulting 18 The specific activity of F-DOPA needs improvement. Furthermore, the preparation process of the labeled precursor used in this method is complex and not resistant to storage. Currently, several... 18 F-DOPA nucleophilic F-18 replacement precursor for use 18 The preparation of F-DOPA can be rapidly achieved using nickel complex precursors developed by Ritter et al. 18 F-DOPA, but the synthesis of this precursor is complex and unstable. J. Am. Chem. Soc. 2012, 134, 42, 17456–17458). ABX developed a nitro precursor, prepared via a three-step reaction. 18 F-DOPA (EP2746250A1, 2014). In addition, several aryl iodonium salts and borate ester precursors have been reported for use in... 18 The preparation of F-DOPA has been carried out, but this type of method has shortcomings such as 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). A novel photocatalytic isotope exchange method can efficiently prepare F-DOPA. 18F-DOPA, however, has a relatively low specific activity that will limit its wider clinical application (Nature Chemistry 2022, 14(2):216-223; Organic Letters 2024; 26(20):4308–4313).

[0004] In conclusion, 18 The difficulty in preparing F-DOPA severely limits its clinical application. Developing a product with a simple reaction, no transition metal involvement, high radiochemical yield, and high specific activity is crucial. 18 The preparation method of F-DOPA is of great significance. Summary of the Invention

[0005] In view of the above-mentioned shortcomings in the prior art, the purpose of the present invention is to provide a 18 Preparation method of F-DOPA and its F-18 labeled precursor.

[0006] To achieve the above-mentioned objectives, the technical solution adopted by this invention is as follows:

[0007] On the one hand, providing a 18 The F-18 marker precursor of F-DOPA has the structural formula shown in Formula I:

[0008]

[0009] In this group, R1 and R2 are hydroxyl protecting groups; R3 is a leaving group; R4 and R5 are hydrogen or amino protecting groups independently; and R6 is a carboxyl protecting group.

[0010] Furthermore, R1 and R2 are independently methyl, allyl, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl, trifluoroacetyl, p-valeryl, benzoyl, p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, 2-tetrahydropyranyl, methoxymethoxymethyl, ethoxymethoxymethyl, 2-ethoxyethyl, benzyl, or R1 and R2 together form methylene, monofluoromethylene, or difluoromethylene; R3 is a leaving group. Groups; R4 and R5 are independently hydrogen or tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, benzyloxycarbonyl, tert-methoxycarbonyl, allyloxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, triphenylmethyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, styryl, tert-butyl, dimethylmethylacetal, amino protecting group; R6 is methyl, ethyl, tert-butyl, benzyl, phenyl.

[0011] Furthermore, R3 is R7, R8, R9, R10, and R11 are independently electron-withdrawing groups such as hydrogen, fluorine, chlorine, nitro, cyano, aldehyde, methoxyformyl, and carbamoyl; or R3 is benzoyl, acetyl, trifluoroacetyl, methanesulfonyl, trifluoromethanesulfonyl, or p-toluenesulfonyl. , , , ; or R3 is , , , pyridazine derivatives; or R3 is , , , , pyridazinone derivatives; or R3 is , , , , Pyrimidine derivatives.

[0012] Furthermore, its chemical structural formula is shown in any of the following:

[0013]

[0014]

[0015]

[0016] .

[0017] On the other hand, providing a 18 The preparation method of F-DOPA adopts 18 The F-18-labeled precursor of F-DOPA is labeled with F-18 via the following reaction. After the F-18 labeling reaction, the protecting group is removed and the product is purified. 18 F-DOPA:

[0018] .

[0019] Furthermore, the photocatalysts used for the photocatalytic labeling reaction include 9-trimethylmethyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate, 9-trimethylmethyl-3,6-di-tert-butyl-10-phenylacridine perchlorate, and riboflavin tetraacetate.

[0020] Furthermore, the light source is blue light in the range of 385-500 nm; the solvent is dichloromethane, dichloroethane, and acetonitrile.

[0021] The beneficial effects of this invention are as follows:

[0022] This invention provides a simple and efficient... 18 The F-DOPA preparation method specifically involves constructing key phenolic precursor compounds and then achieving 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 potential for automated production. Radioactive tracers synthesized using this method. 18 F-DOPA has high specific activity, high chemical purity, and high radioactive purity, and is effective against... 18 The clinical promotion of F-DOPA is of great value. Attached Figure Description

[0023] Figure 1 The radioHPLC chromatogram of the F-18-labeled reaction solution of precursor 2;

[0024] Figure 2 RadioHPLC chromatogram of the F-18-labeled reaction solution of precursor 3;

[0025] Figure 3 RadioHPLC chromatogram of the F-18 labeled reaction solution of precursor 5;

[0026] Figure 4 RadioHPLC chromatogram of the F-18 labeled reaction solution of precursor 6;

[0027] Figure 5 RadioHPLC chromatogram of the F-18 labeled reaction solution of precursor 7;

[0028] Figure 6 RadioHPLC chromatogram of the F-18 labeled reaction solution of precursor 8;

[0029] Figure 7 RadioHPLC chromatogram of the F-18 labeled reaction solution of precursor 9;

[0030] Figure 8 RadioHPLC chromatogram of the F-18 labeled reaction solution of precursor 10;

[0031] Figure 9 RadioHPLC chromatogram of the F-18 labeled reaction solution for precursor 14;

[0032] Figure 10 RadioHPLC chromatogram of the F-18 labeled reaction solution for precursor 16;

[0033] Figure 11 RadioHPLC chromatogram of the F-18 labeled reaction solution of precursor 22;

[0034] Figure 12 RadioHPLC chromatogram of the F-18 labeled reaction solution of precursor 26;

[0035] Figure 13 RadioHPLC chromatogram of the F-18 labeled reaction solution of precursor 43;

[0036] Figure 14 RadioHPLC chromatogram of F-18 labeled reaction solution of precursor 58;

[0037] Figure 15 RadioHPLC chromatogram of the F-18 labeled reaction solution of precursor 60. Detailed Implementation

[0038] The specific embodiments of the present invention are described below to enable those skilled in the art to understand the present invention. However, it should be understood that the present invention is not limited to the scope of the specific embodiments. For those skilled in the art, various changes are obvious as long as they are within the spirit and scope of the present invention as defined and determined by the appended claims. All inventions utilizing the concept of the present invention are protected.

[0039] Example 1

[0040] Synthesis of Precursor 1

[0041]

[0042] Synthesis of compound 1-a: 2-hydroxy-4,5-dimethoxybenzaldehyde (2.72 g, 10 mmol, 1 eq) and 1,8-diazacyclo[5,4,0]undecene-7 (1.85 g, 12 mmol, 1.2 eq) were dissolved in dichloromethane (50 mL). The mixture was stirred in an ice bath for 20 minutes. Trimethyl methyl (±)-BOC-A-phosphonoglycine (3.57 g, 12 mmol, 1.2 eq) was added in portions, and the mixture was stirred at room temperature for 4 hours. TLC showed that the starting materials had reacted almost completely (PE : EA = 2 : 1). The reaction was quenched with saturated ammonium chloride water (20 mL). The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to a minimum amount of solvent. The mixture was then slurried with petroleum ether to obtain a white precipitate, which was directly used in the next reaction. The raw material was dissolved in an appropriate amount of methanol, and a catalyst amount of Pd / C (10%) was added. A hydrogen balloon was connected, and hydrogen was purged three times. The reaction was carried out overnight at room temperature. The product was filtered and concentrated to obtain a white solid product. 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).

[0043] 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), followed by the addition of triethylamine (505 mg, 5 mmol, 5 eq) and copper acetate (218 mg, 1.2 mmol, 1.2 eq). The mixture was stirred at room temperature for 24 hours. A 1 M citric acid aqueous solution (40 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic layers were combined, washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 6:1) to give 179.3 mg of a white solid, yield 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).

[0044] Synthesis of Precursor 2

[0045]

[0046] 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), and potassium carbonate (276 mg, 2 mmol, 2 eq) was added. The mixture was reacted overnight at room temperature. After washing with saturated sodium chloride (100 mL), 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 evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 6:1) to give 281.3 mg of a white solid, in 61.5% yield. 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).

[0047] Precursor 3 was synthesized using the same method as precursor 1, but with different raw materials. It is a white solid with a yield of 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).

[0048] Precursors 4, 5, 6, 7, 8, 9, 10, 11, and 12 were synthesized by changing the raw materials according to the synthesis method of precursor 2.

[0049] 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).

[0050] 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).

[0051] 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.

[0052] 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).

[0053] Precursor 8, white solid, yield 63.2%. 1H 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).

[0054] 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.

[0055] Precursor 10, white solid, yield 63.1%. 1 H NMR (400 MHz, DMSO- d6) 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).

[0056] 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).

[0057] 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.

[0058] Synthesis of precursor 13

[0059]

[0060] 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), and triethylamine (202 mg, 2 mmol, 2 eq) was added. The mixture was reacted overnight at room temperature. 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 evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 6:1) to give 282.1 mg of a white solid, in 68.3% yield. 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).

[0061] Precursors 14, 15, 16, 17, 18, 19, 20, 21, and 22 were synthesized by changing the raw materials according to the synthesis method of precursor 13.

[0062] 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).

[0063] 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).

[0064] 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).

[0065] 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).

[0066] 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).

[0067] 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).

[0068] 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).

[0069] 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).

[0070] Synthesis of precursor 23

[0071]

[0072] 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), and cesium carbonate (24.5 g, 75 mmol, 1.5 eq) was added. The mixture was reacted at 110 °C for 24 h. After washing with saturated sodium chloride (200 mL), 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 purified by silica gel column chromatography (PE:EA = 5:1) to give 6.69 g of a white solid, yield 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).

[0073] 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. The mixture was reacted overnight at room temperature. After washing with saturated sodium chloride (200 mL), the mixture was extracted with dichloromethane (50 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and slurried with petroleum ether and dichloromethane to give 3.4 g of a white solid product, yield: 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).

[0074] Synthesis of compound 23-d: 23-b (3.68 g, 10 mmol, 1 eq) and 1,8-diazacyclic [5,4,0]undecene-7 (1.85 g, 12 mmol, 1.2 eq) were dissolved in dichloromethane (50 mL), stirred in an ice bath for 20 minutes, and (±)-BOC-A-phosphonoglycine trimethyl ester (3.57 g, 12 mmol, 1.2 eq) were added in portions. The reaction was then stirred at room temperature for 4 hours. TLC showed that the starting materials were basically completely reacted (PE : EA = 2 : 1). The reaction was quenched by adding saturated ammonium chloride water (20 mL), and the organic phase was washed successively with water and saturated sodium chloride. After drying with anhydrous sodium sulfate, the product was filtered, concentrated to a minimum amount of solvent, and slurried with petroleum ether to obtain a white precipitate, which was directly used in the next reaction. The starting materials were dissolved in an appropriate amount of methanol, and a catalytic amount of Pd / C (10%) was added. A hydrogen balloon was connected, and hydrogen was purged three times. The reaction was carried out overnight at room temperature. The product was filtered and concentrated to obtain a white solid product. The product was then 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).

[0075] 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), and triethylamine (101 mg, 1 mmol, 2 eq) was added. The mixture was reacted overnight at room temperature. 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 evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA = 6:1) to give 118.1 mg of a white solid, in 39.4% yield. 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).

[0076] Synthesis of precursor 32:

[0077]

[0078] Synthesis of 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), and potassium carbonate (10.4 g, 75 mmol, 1.5 eq) was added. The mixture was reacted at 100 °C for 24 h. After washing with saturated sodium chloride (200 mL), 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 then purified by silica gel column chromatography (PE:EA = 5:1) to give 6.47 g of a white solid, yield 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).

[0079] 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. The reaction was carried out in an ice bath for 4 hours. The reaction was quenched with ice-cold methanol, and the solvent was removed by concentration under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, concentrated under reduced pressure, and slurried with petroleum ether and dichloromethane to give 1.9 g of a brown solid product, which was used directly 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. The reaction was carried out overnight at room temperature. Add saturated sodium chloride (200 mL), extract with ethyl acetate (100 mL × 3), combine the organic layers, dry with anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, and purify 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).

[0080] Synthesis of precursor 32: 32-c (0.51 g, 1 mmol, 1 eq) and 1,8-diazacyclic [5,4,0]undecene-7 (0.185 g, 1.2 mmol, 1.2 eq) were dissolved in dichloromethane (50 mL). The mixture was stirred in an ice bath for 20 minutes. Trimethyl methyl (±)-BOC-A-phosphonoglycine (0.357 g, 1.2 mmol, 1.2 eq) was added in portions, and the mixture was stirred at room temperature for 4 hours. TLC showed that the reactants were essentially completely reacted (PE : EA = 2 : 1). The reaction was quenched with saturated ammonium chloride water (20 mL). The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to a minimum amount of solvent. Petroleum ether was added and the mixture was stirred to obtain a white precipitate, which was directly used in the next reaction. The reactants were dissolved in an appropriate amount of methanol, and a catalytic amount of Pd / C (10%) was added. A hydrogen balloon was connected, and hydrogen was purged three times. The mixture was reacted overnight at room temperature. The product was filtered and concentrated to obtain a white solid product, which was then purified by chiral separation to obtain a white solid product. 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).

[0081] Precursor 30 is synthesized using the same method as precursor 32, but with different raw materials. It is a 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).

[0082] Precursor 33 was synthesized using the same method as precursor 32, but with different raw materials. It is a 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).

[0083] Precursor 34 was synthesized using the same method as precursor 32, but with different raw materials. It is a 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).

[0084] Synthesis of precursor 43

[0085]

[0086] Synthesis of compound 43-a: Methyl (S)-(2-((tert-butoxycarbonyl)amino)-3-(3,4-dihydroxyphenyl)propionate (3.11 g, 10 mmol, 1 eq) and chloromethyl ethyl ether (2.85 g, 30 mmol, 3 eq) were dissolved in tetrahydrofuran (100 mL), and 3.88 g (30 mmol, 3 eq) was added. The reaction 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 sequentially. The organic layer was washed sequentially with distilled water (2 x 100 mL), 5% aqueous acetic acid solution (2 x 100 mL), 10% aqueous potassium carbonate solution (2 x 100 mL), and saturated brine (3 x 100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 3.61 g of a yellow oil, yield: 84.3%.

[0087] 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 min. A solution of [bis(trifluoroacetoxy)iodo]benzene (3.23 g, 7.5 mmol, 1.5 eq) in dichloromethane (50 mL) was added dropwise under nitrogen protection. The reaction mixture was reacted at room temperature for 3 h, and the reaction mixture was washed successively with 10% potassium carbonate aqueous solution (2 x 100 mL), 5% sodium sulfite aqueous solution (2 x 100 mL), and water (150 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. Column chromatography (PE:EA = 5:1) was used to purify the mixture, yielding 1.38 g of a pale yellow solid (yield: 49.7%). 1 H NMR (400 MHz, Chloroform- d ) δ7.54 (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).

[0088] Synthesis of compound 43-c: Compound 43-b (1.107 g, 2 mmol, 1 eq), potassium acetate (0.39 g, 4 mmol, 2 eq), boron pinacol ester (1.02 g, 4 mmol, 2 eq), and Pd(dppf)₂Cl₂ (0.165 g, 0.2 mmol, 0.1 eq) 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 sequentially. The organic layer was washed with saturated brine (4 x 100 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was dissolved in methanol (20 mL), and hydrogen peroxide (33%, 10 mL) was added. The mixture was reacted at room temperature for 1 hour. Add ethyl acetate (200 mL) and water (150 mL), wash the organic layer with saturated brine (4 x 100 mL), dry the organic phase with magnesium sulfate, filter and concentrate, and purify by column chromatography (PE:EA = 5:1) to give 0.45 g of pale yellow solid product.

[0089] 1 H NMR (400 MHz, Chloroform- d ) δ 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).

[0090] Precursor 43 was synthesized using the same method as precursor 2, but with different raw materials. It is a white solid with a yield of 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.

[0091] Precursor 44 was synthesized using the same method as precursor 2, but with different raw materials. It is a white solid with a yield of 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.

[0092] Synthesis of precursor 55

[0093]

[0094] Synthesis of precursor 55: 2-(tert-butyl)-4,5-dichloropyridazine-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) and reacted at 70 °C for 4 hours. After the reaction was completed by TLC (PE:EA = 2:1), water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 100 mL). The organic phase was then washed with saturated brine, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 86 mg of pale yellow solid, yield: 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.

[0095] Precursors 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, and 68 were synthesized by changing the raw materials according to the synthesis method of precursor 55.

[0096] 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.

[0097] 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.

[0098] Precursor 58: pale yellow solid, yield: 49.6%. 1H 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.

[0099] 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). 13C 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] Precursor 63: white solid, yield: 57.6%. 1H 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] Precursor 68: yellow solid, yield: 34.2%. 1H 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.

[0109] Example 2

[0110] 18 F-18 labeling of F-DOPA precursor compounds and 18 Preparation of F-DOPA:

[0111]

[0112] 18 Synthesis of F-DOPA: 0.01 mmol of the precursor, 2 mg of 9-trimethylyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate (CAS NO.1810004-87-5), were placed in a V-type reaction flask. 0.5 ml of dichloromethane or dichloroethane was added, followed by the addition of pretreated... 18 F - An important marker intermediate can be generated by irradiating the solution with a 456 nm LED light for 15 minutes. 18 FI. After removing the reaction solvent, the intermediate... 18 FI can be prepared by removing the protecting group with concentrated hydrochloric acid, concentrated sulfuric acid, or hydrogen iodide under heating or no heating conditions, then adjusting the pH of the reaction solution to 6-7, and finally purifying by HPLC. 18 The F-DOPA precursor's F-18 labeling chemical conversion rate was determined by radioactive HPLC, as shown in the table below. (ND: Not detected). HPLC conditions: 70% MeCN: 30% KK (potassium phosphate buffer, pH: 8.0), flow rate: 1 ml / min.

[0113]

[0114] In summary, this invention provides a simple and efficient method. 18 The F-DOPA preparation method specifically involves constructing key phenolic precursor compounds and then achieving 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 potential for automated production. Radioactive tracers synthesized using this method. 18 F-DOPA has high specific activity, high chemical purity, and high radioactive purity, and is effective against... 18 The clinical promotion of F-DOPA is of great value.

[0115] 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 invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. A kind 18 The preparation method of F-DOPA is characterized by, use 18 F-DOPA's F-18-labeled precursor is photocatalytically labeled using the following reaction formula to achieve F-18 labeling. After the F-18 labeling reaction, the protecting group is removed and the product is purified. 18 F-DOPA: ； In the reaction formula, the F-18 labeled phenolic precursor compound represented by Formula I is selected from any one of the following compounds: ； ； ； ； ； The photocatalyst used for the photocatalytic labeling reaction is selected from 9-mesinetrimethyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate; the light source is blue light of 385-500 nm; and the solvent is dichloromethane, dichloroethane, or acetonitrile.

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