Method for preparing < 18 > F-m-fluorobenzylguanidine

Abstract

The invention discloses a method for preparing < 18 > F-m-fluorobenzylguanidine, and solves the technical problems of complex reaction steps, low radiochemical yield and low specific activity in a method for synthesizing < 18 > F-mFBG. The invention comprises a phenolic ether precursor compound of a core skeleton corresponding to 18F-mFBG, a synthesis method of the phenolic ether precursor compound, and a method for realizing F-18 labeling and preparation of mFBG by using the precursor compound. Specifically, 18F-mFBG labeling and preparation are realized by constructing a key phenolic ether precursor compound and performing 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 18F-mFBG synthesized by the method is high in specific activity, chemical purity and radioactive purity, and has important value for clinical popularization of targeted NET molecular function PET imaging.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology and specifically relates to a method for preparing 18 F-meta-Fluorobenzylguanidine method. Background Art

[0002] Norepinephrine transporter (NET) is a transmembrane protein responsible for the uptake of norepinephrine in synaptic nerve endings and adrenal chromaffin cells. Its expression changes are closely related to the occurrence and development of various heart diseases and neuroendocrine tumors. NET is an important target for molecular imaging and radionuclide therapy of various neuroendocrine tumors, and is also an important functional molecular imaging target for diseases related to cardiac autonomic dysfunction, such as sudden cardiac death, heart failure, diabetic cardiac autonomic neuropathy, arrhythmia, etc.

[0003] Currently, the commonly used NET-targeted radioactive drugs in clinical practice are 123 I-metaiodobenzylguanidine ( 123 I-mIBG), because I-123 is a single-photon probe, it can only be imaged by planar or single-photon emission computed tomography (SPECT), resulting in low image resolution and slow metabolism. 123 I-mIBG imaging still has some practical limitations. 18 F-Meta-Fluorobenzylguanidine ( 18 F-mFBG) is a mIBG analogue, which can also effectively enrich NET-positive cells through the specific uptake of NET. Existing basic research and clinical application data show that 18 F-mFBG has a significantly better imaging effect than PET in myocardial and NET-positive neuroendocrine tumors. 123 The imaging efficacy of I-mIBG (J Nucl Cardiol, 2022, 29, 3179-3188; Clin Cancer Res (2014) 20 (8): 2182-2191; Eur J Nucl Med Mol Imaging 50, 3097-3106 (2023). 18 F-mFBG NET molecular functional imaging has important clinical value in the diagnosis of cardiac autonomic dysfunction-related diseases and NET-positive neuroendocrine tumors.

[0004] However, the current synthesis 18The F-mFBG method has the disadvantages of complex reaction steps, low radiochemical yield, and low specific activity. The indirect labeling method reported by Zhang et al. requires about 3 hours of preparation time, a corrected radiochemical yield of 11±2%, and a specific activity of 505mCi / μmol (Eur J Nucl Med Mol Imaging, 2014, 41, 322-332). The diaryliodonium salt precursor F-18 labeling strategy reported by Hu et al. requires 56±2 minutes of preparation time, a corrected radiochemical yield of 31%, and a specific activity of >657mCi / μmol (ACS Chem Neurosci, 2015, 6, 1870-1879). The pinacol boronate precursor F-18 labeling strategy reported by Preshlock et al. requires >60 minutes of preparation time, a corrected radiochemical yield of 41±2%, and a specific activity of 400-620mCi / μmol (Chem Commun, 2016, 52, 8361-8364). The F-18 labeling strategy for high-valent iodine ylide precursors reported by Rotstein, Wang Lu and others required a preparation time of 79-99 minutes, an uncorrected radiochemical yield of 7-28%, and a specific activity of >2Ci / μmol (ChemSci, 2016, 7, 4407-4417 and CN112778163A). 18 The difficulty in preparing F-mFBG has greatly limited its clinical application. 18 The preparation method of F-mFBG is of great significance. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing 18 Methods to Solve the Synthesis of F-Meta-Fluorobenzylguanidine 18 The F-mFBG method has technical problems such as complex reaction steps, low radiochemical yield and low specific activity.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] The present invention provides a preparation 18 F-meta-fluorobenzylguanidine method, comprising 18 A phenol ether precursor compound corresponding to the core skeleton of F-mFBG and a synthesis method thereof, as well as a method for realizing F-18 labeling and preparation of mFBG using the precursor compound.

[0008] Furthermore, the phenol ether precursor compound has a structural formula as shown in Formula I:

[0009]

[0010] Among them, R1 and R2 are hydrogen or independently substituted with fluorine, chlorine, bromine, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, formate, formamide, alkyl, substituted alkyl, aryl, substituted aryl, etc. at any position of the benzene ring; R3, R4, R5, and R6 are independently hydrogen or any amino protecting group.

[0011] Furthermore, in the structural formula of the phenol ether precursor compound, R1 and R2 are hydrogen, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, formate, or formamide; R3, R4, R5, and R6 are independently hydrogen or an amino protecting group such as tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, benzyloxycarbonyl, tert-methoxycarbonyl, allyloxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, styryl, tert-butyl, or dimethylformal.

[0012] Furthermore, in the structural formula of the phenol ether precursor compound, R1 and R2 are hydrogen, fluorine, chlorine, methyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy; R3 is hydrogen or tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, tert-butyl, or dimethyl acetal; R4 is tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, benzyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl, phthaloyl, p-Toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, tert-butyl, dimethylformal; R5 and R6 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.

[0013] Furthermore, in the structural formula of the phenol ether precursor compound, R1 and R2 are hydrogen; R3 is tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, dimethylformal, trityl, or tert-butyl; R4 is tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, trifluoroacetyl, or dimethylformal; R5 and R6 are independently hydrogen or tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, trifluoroacetyl, or dimethylformal, or R5 and R6 together with the protected amino group form a

[0014]

[0015] Furthermore, the structure of the phenol ether precursor compound is characterized by:

[0016]

[0017]

[0018]

[0019]

[0020] Furthermore, the precursor compound is prepared by the following reaction: 18 F-Meta-Fluorobenzylguanidine:

[0021]

[0022] The photocatalyst used for the photocatalytic labeling reaction includes 9-striphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate (CAS NO.1810004-87-5), 9-striphenyl-3,6-di-tert-butyl-10-phenylacridine perchlorate, and riboflavin tetraacetate (CAS NO.752-13-6), preferably 9-striphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate (CAS NO.1810004-87-5); the solvent is dichloromethane or dichloroethane, and the protective group is removed after the F-18 labeling reaction and separated and purified to obtain 18 F-meta-Fluorobenzylguanidine.

[0023] Based on the above technical solution, the embodiments of the present invention can at least produce the following technical effects:

[0024] The preparation provided by the present invention 18 The method of preparing F-meta-fluorobenzylguanidine is specifically to construct a key phenol ether precursor compound and realize it through a simple and efficient photocatalytic deoxyfluorination reaction of aromatic hydrocarbons. 18 Preparation of F-mFBG. This method has few steps, high yield, simple operation, good reproducibility, and good automation production potential. Radioactive tracers synthesized using this method 18 F-mFBG has high specific activity, high chemical purity and high radioactivity purity, and is of great value in achieving clinical promotion of targeted NET molecular function PET imaging. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the structures shown in these drawings without paying creative work.

[0026] Figure 1 The F-18 labeled reaction solution radioactive HPLC spectrum of the precursor 1 of the present invention;

[0027] Figure 2 The precursor 1 of the present invention is prepared by purification after F-18 labeling reaction. 18 Radio-HPLC spectrum of F-mFBG. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. In addition, the technical solutions between the various embodiments can be combined with each other, but they must be based on the ability of ordinary technicians in this field to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0029] Example 1

[0030] Synthesis of precursors:

[0031]

[0032] Synthesis of compound 1-a: (3-phenoxyphenyl)methylamine (238 mg, 1.20 mmol, 1.0 eq) and N,N'-di-Boc-1H-1-guanidinopyrazole (410 mg, 1.32 mmol, 1.1 eq) were dissolved in acetonitrile (10 mL), potassium carbonate (249 mg, 1.80 mmol, 1.5 eq) was added, and then stirred at room temperature overnight. TLC showed that (PE: EA = 5: 1) the raw materials were basically reacted. Water (20 mL) was added to quench the reaction, and ethyl acetate was used for extraction (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and separated and purified by silica gel column chromatography (PE: EA = 15: 1) to obtain a white solid (482 mg) with a yield of 91.1%. 1HNMR(400MHz,Chloroform-d)δ11.53(s,1H),8.59(d,J=5.4Hz,1H),7.37–7.27(m,3H),7.11(tt,J=7.3,1.1Hz,1H),7.06– 6.98(m,3H),6.97(t,J=2.1Hz,1H),6.91(ddd,J=8.2,2.6,0.9Hz,1H),4.60(d,J=5.2Hz,2H),1.51(s,9H),1.48(s,9H).13C NMR(100MHz,Chloroform-d)δ163.58,157.67,156.90,156.15,153.21,139.35,130.05 ,129.79,123.45,122.38,119.08,118.03,117.77,83.23,79.43,44.69,28.30,28.08.

[0033] Synthesis of Precursor 1: Compound 1-a (250 mg, 0.57 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), DMAP (345 mg, 2.85 mmol, 5 eq) and Boc anhydride (495 mg, 2.28 mmol, 4 eq) were added, and then stirred at room temperature for 2 h. TLC showed that (PE: EA = 5: 1) the raw material was basically reacted. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and purified by silica gel column chromatography (PE: EA = 15: 1) to obtain a colorless transparent oil (350 mg) with a yield of 96.4%. 1 H NMR(400MHz,Chloroform-d)δ7.31(dd,J=8.5,7.2Hz,2H),7.23(d,J=7.9Hz,1H),7.15(d,J=7.7Hz,1H),7.10–7.0 2(m,2H),7.00–6.94(m,2H),6.87(dd,J=8.1,2.4Hz,1H),5.00(s,2H),1.48(s,9H),1.46(s,18H),1.38(s,9H).13C NMR(100MHz,Chloroform-d)δ157.38,157.32,157.08,151.19,147.33,144.42,139.56,129.71,1 29.51,123.10,122.53,118.70,118.29,117.66,83.81,83.76,82.01,49.92,28.00,27.87,27.83.

[0034]

[0035] Synthesis of compound 3-a: 3-(Aminomethyl)phenol (246 mg, 2.00 mmol, 1.0 eq) and N,N'-di-Boc-1H-1-guanidinopyrazole (682 mg, 2.20 mmol, 1.1 eq) were dissolved in acetonitrile (20 mL), potassium carbonate (414 mg, 3.00 mmol, 1.5 eq) was added, and then stirred at room temperature overnight. TLC showed that (PE: EA = 5: 1) the raw materials were basically reacted. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and separated and purified by silica gel column chromatography (PE: EA = 10: 1) to obtain a white solid (712 mg) with a yield of 97.5%. 1H NMR (400MHz, Chloroform-d) δ11.55(s,1H),8.67(t,J=5.6Hz,1H),7.11(t,J=7.7Hz,1H),6.74(d,J= 7.6Hz,1H),6.69(d,J=8.3Hz,2H),6.34(s,1H),4.54(d,J=5.4Hz,2H),1.49(s,9H),1.47(s,9H).13C NMR(100MHz,Chloroform-d)δ163.33,156.43,156.34,153.18,138.75,129.69,119.02,114.60,114.44,83.38,79.69,44.51,28.21,28.08.

[0036] Synthesis of compound 3-b: Dissolve the raw material 3-a (300 mg, 0.82 mmol, 1.0 eq) and m-chlorophenylboronic acid (143 mg, 0.90 mmol, 1.1 eq) in dichloroethane (15 mL), add copper acetate (180 mg, 0.90 mmol, 1.1 eq) and triethylamine (173 ul, 1.23 mmol), react at room temperature for 24 h, and monitor the reaction by TLC (PE: EA = 5: 1). Add 1M citric acid aqueous solution (20 mL), extract with dichloromethane (20 mL × 3), combine the organic layers, wash with saturated sodium chloride aqueous solution (60 mL × 1), dry over anhydrous sodium sulfate, filter, decompress and spin-dry the solvent, separate and purify by silica gel column chromatography (PE: EA = 15: 1), and obtain a colorless transparent oil (105 mg), with a yield of 26.8%. 1H NMR (400MHz, Chloroform-d) δ11.53(s,1H),8.61(t,J=5.3Hz,1H),7.32(t,J=7.9Hz,1H),7.28–7.21(m,1H),7.08(tdd,J= 13C NMR(100MHz,Chloroform-d)δ163.57,158.00,156.76,156.19,153.22,139.68,135.10,130.52 ,130.24,123.42,123.15,119.05,118.54,118.28,116.86,83.30,79.46,44.57,28.30,28.07.

[0037] Synthesis of precursor 3: The raw material 3-b (80 mg, 0.17 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), DMAP (103 mg, 0.85 mmol, 5 eq) and Boc anhydride (147 mg, 0.68 mmol, 4 eq) were added, and then stirred at room temperature for 2 h. TLC showed that (PE: EA = 5: 1) the raw material was basically reacted. Water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. Purification was performed by silica gel column chromatography (PE: EA = 15: 1) to obtain a colorless transparent oil (110 mg) with a yield of 96.5%. 1H NMR(400MHz,Chloroform-d)δ7.27(d,J=7.7Hz,1H),7.25-7.17(m,2H),7.08-7.01(m,2H),6.93(t,J=2.2H z,1H),6.87(dddd,J=16.7,8.3,2.4,1.0Hz,2H),5.01(s,2H),1.48(s,9H),1.46(s,18H),1.38(s,9H).13C NMR(100MHz,Chloroform-d)δ158.45,157.34,156.17,151.15,147.31,144.48,139.90,135.02,130.47,1 29.72,123.32,123.06,118.75,118.58,118.23,116.50,83.90,83.79,82.06,49.90,27.99,27.87,27.84.

[0038] Synthesis of Precursor 4: Synthesized by changing the raw materials according to the synthesis method of Precursor 1. Pale yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.29–7.22(m,3H),7.18–7.15(m,1H),7.04–7.03(m,1H),6.93–6.89( m,2H),6.87(ddd,J=8.1,2.6,1.0Hz,1H),5.00(s,2H),1.48(s,9H),1.45(s,18H),1.39(s,9H).13C NMR(100MHz,Chloroform-d)δ157.34,156.70,156.01,151.18,147.31,144.40,139.73,129.69,1 29.65,128.08,122.92,119.85,118.31,117.71,83.89,83.77,82.05,49.90,27.99,27.86,27.84.

[0039] Synthesis of Precursor 6: Synthesized by changing the raw materials according to the synthesis method of Precursor 3. Colorless oil. 1H NMR (400MHz, Chloroform-d) δ7.27–7.24(m,2H),7.18(dt,J=7.8,1.3Hz,1H),7.03(t,J=2.0Hz,1H),6.88(dtd,J=4.8,2.5,1.1Hz,2H),6.73( t,J=2.2Hz,1H),6.66(dt,J=1.5,0.7Hz,1H),5.01(s,2H),3.77-3.72(m,1H),2.28(d,J=0.7Hz,3H),1.48(s,9H),1.46(s,18H),1.37(s,9H).

[0040] Synthesis of Precursor 7: Synthesized by changing the raw materials according to the synthesis method of Precursor 3. Colorless oil. 1 H NMR(400MHz,Chloroform-d)δ7.28–7.26(m,2H),7.15(dt,J=7.8,1.3Hz,1H),7.01(t,J=2.0Hz,1H),6.88(dtd,J=4.8,2.5,1.1Hz,2H),6.73( t,J=2.2Hz,1H),6.57(dt,J=1.6,0.9Hz,1H),5.12(s,2H),3.70-3.82(m,1H),2.29(d,J=0.6Hz,3H),1.49(s,9H),1.45(s,18H),1.36(s,9H).

[0041] Synthesis of Precursor 8: Synthesized by changing the raw materials according to the synthesis method of Precursor 3. Pale yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.75(ddd,J=7.9,2.5,0.9Hz,1H),7.54–7.42(m,2H),7.07(dddd,J=8.2,3.0,1. 9,1.0Hz,2H),6.96–6.86(m,2H),4.90(t,J=1.0Hz,2H),3.89(s,3H),1.49(s,9H),1.44(s,18H),1.33(s,9H).

[0042] Synthesis of Precursor 10: Synthesized by changing the raw materials according to the synthesis method of Precursor 3. Pale yellow oil. 1H NMR(400MHz,Chloroform-d)δ7.31(d,J=6.8Hz,1H),7.28–7.11(m,2H),7.06–7.01(m,2H),6.91(t,J=2. 1Hz,1H),6.89(dddd,J=15.5,7.3,1.9,1.1Hz,2H),5.02(s,2H),1.49(s,9H),1.45(s,18H),1.37(s,9H).

[0043] Synthesis of Precursor 13: Synthesized by changing the raw materials according to the synthesis method of Precursor 3. Pale yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.53–7.43(m,2H),7.34–7.27(m,2H),7.14–7.03(m, 2H),6.96–6.86(m,2H),4.90(t,J=1.0Hz,2H),3.00(s,6H),1.46(d,J=4.1Hz,37H).

[0044] Synthesis of Precursor 14: Synthesized by changing the raw materials according to the synthesis method of Precursor 3. Pale yellow oil. 1 H NMR (400MHz, Chloroform-d) δ7.39–7.20(m,18H),7.15–7.06(m,2H),7.03–6.96(m,2H),6.96–6.83(m,2H),4.92(t,J=1.0Hz,2H),1.52–1.45(d,27H).

[0045] Synthesis of Precursor 15: Synthesized by changing the raw materials according to the synthesis method of Precursor 3. Pale yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.33(dt,J=19.8,7.9Hz,3H),7.15–7.04(m,2H),7.03 –6.84(m,4H),4.76(t,J=1.0Hz,2H),1.53–1.49(s,18H),1.47(s,9H),1.38(s,9H).

[0046] Synthesis of Precursor 21: Synthesized by replacing the raw materials according to the synthesis method of Precursor 3. Pale yellow oil. 1H NMR (400MHz, Chloroform-d) δ7.39–7.21 (m, 18H), 7.15–7.06 (m, 2H), 7.03–6.83 (m, 4H), 4.91–4.83 (m, 6H), 2.96 (s, 6H), 1.53–1.49 (s, 9H).

[0047] Synthesis of Precursor 30: Synthesized by replacing the raw materials according to the synthesis method of Precursor 3. Pale yellow oil. 1H NMR (400 MHz, Chloroform-d) δ7.31 (td, J = 8.1, 4.0 Hz, 2H), 6.98–6.85 (m, 3H), 6.71–6.63 (m, 1H), 4.90 (t, J = 1.0 Hz, 2H), 1.54 (s, 18H), 1.46 (d, J = 4.1 Hz, 18H).

[0048] Synthesis of Precursor 31: Synthesized by changing the raw materials according to the synthesis method of Precursor 3. White solid. 1 H NMR(400MHz,Chloroform-d)δ7.36–7.27(m,2H),7.07(ddq,J=8.1,2.1,1.0Hz,1H),7.02–6.95(m,1H ),6.92–6.86(m,2H),6.74–6.68(m,2H),4.94(t,J=1.0Hz,2H),1.54(s,18H),1.46(d,J=4.1Hz,18H).

[0049] Synthesis of Precursor 33: Synthesized by changing the raw materials according to the synthesis method of Precursor 3. White solid. 1 H NMR(400MHz,Chloroform-d)δ7.31(t,J=8.0Hz,2H),7.07(ddt,J=8.1,2.2,1.0Hz,2H) ,6.96–6.87(m,4H),4.90(t,J=1.0Hz,4H),1.56(s,36H),1.47(s,18H),1.46(s,18H).

[0050] Synthesis of Precursor 36a: Synthesized by changing the raw materials according to the synthesis method of Precursor 3. White solid. 1 H NMR (400MHz, Chloroform-d) δ7.46–7.37(m,2H),7.17–7.08(m,2H),6.96–6.87(m,4H),4.89(s,8H),4.81(t,J=1.0Hz,4H),2.96(s,12H),1.46(s,36H).

[0051] Embodiment 2:

[0052] F-18 markings and 18 Synthesis of F-mFBG control compound:

[0053]

[0054] Synthesis of compound 39: (3-fluorophenyl)methylamine hydrochloride (125 mg, 0.77 mmol, 1.0 eq) and N,N'-di-Boc-1H-1-guanidinopyrazole (263 mg, 0.85 mmol, 1.1 eq) were dissolved in acetonitrile (10 mL), potassium carbonate (266 mg, 1.93 mmol, 2.5 eq) was added, and then stirred at room temperature for overnight reaction. TLC showed that (PE:EA=5:1) the raw materials were basically reacted. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and purified by silica gel column chromatography (PE:EA=15:1) to obtain a white solid (263 mg) with a yield of 92.3%. 1 H NMR (400MHz, Chloroform-d) δ11.54(s,1H),8.62(t,J=5.2Hz,1H),7.30(td,J=7.9,5.9Hz,1H),7.08(ddd,J=7.6,1.6,0.9H z,1H),7.03(dt,J=9.7,2.1Hz,1H),6.98(ddt,J=8.6,7.6,1.4Hz,1H),4.63(d,J=5.3Hz,2H),1.51(s,9H),1.49(s,9H).19F NMR(377MHz,Chloroform-d)δ-112.70.13C NMR(100MHz,Chloroform-d)δ163.56,162.99(d,J=246.3Hz),156.22,153.24,139.95(d,J=7.3Hz),130.25(d,J=8.3H z), 123.27 (d, J = 2.9Hz), 114.71 (d, J = 17.5Hz), 114.50 (d, J = 16.8Hz), 83.35, 79.50, 44.35 (d, J = 1.9Hz), 28.29, 28.07.

[0055] Synthesis of compound 40: The raw material 39 (200 mg, 0.54 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), DMAP (328 mg, 2.70 mmol, 5 eq) and Boc anhydride (468 mg, 2.16 mmol, 4 eq) were added, and then stirred at room temperature for 2 h. TLC showed that (PE: EA = 5: 1) the raw material was basically reacted. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. Purification was performed by silica gel column chromatography (PE: EA = 15: 1) to obtain a colorless transparent oil (283 mg) with a yield of 91.7%. 1H NMR(400MHz,Chloroform-d)δ7.28–7.22(m,1H),7.15(dt,J=7.6,1.3Hz,1H),7.11(dt,J=9 .8,2.2Hz,1H),6.96–6.91(m,1H),5.02(s,2H),1.49(s,9H),1.48(s,18H),1.40(s,9H).19F NMR(377MHz,Chloroform-d)δ-113.64.13CNMR(100MHz,Chloroform-d)δ162.86(d,J=245.3Hz),157.32,151.12,147.31,144.47,140.09(d,J=7.3Hz), 129.64(d,J=8.2Hz),123.22(d,J=2.9Hz),114.41(d,J=21.9Hz),114.02(d ,J=21.1Hz),84.00,83.87,82.13,49.72(d,J=2.0Hz),27.99,27.88,27.83.

[0056] Synthesis of mFBG: The raw material 40 (63 mg, 0.17 mmol, 1.0 eq) was dissolved in 6N hydrochloric acid (2 mL), then heated to 100°C and stirred for 2 h. TLC showed that (PE:EA=5:1) the raw material was basically reacted. The solvent was dried under reduced pressure, the crude product was dissolved in water (1 mL), and freeze-dried to obtain a white solid (30 mg) with a yield of 86.2%. 1 H NMR (400MHz, Deuterium Oxide) δ7.35 (ddd, J=9.2, 6.9, 4.0Hz, 1H), 7.09 (d, J=7.7Hz, 1H), 7.03 (t, J=8.0Hz, 2H), 4.38 (s, 2H). 19F NMR (377MHz, Deuterium Oxide)δ-113.37.13C NMR(100MHz,DeuteriumOxide)δ162.82(d,J=243.9Hz),156.96,138.74(d,J=7.3Hz),130.64(d, J=8.5Hz), 122.54(d,J=2.9Hz), 114.61(d,J=21.2Hz), 113.54(d,J=22.5Hz), 43.95(d,J=2.0Hz).

[0057] Implementation 3

[0058] F-18 labeling and purification of precursors:

[0059]

[0060]

[0061] 18 Synthesis and preparation of F-mFBG: Take 0.01mmol of precursor, 2mg of 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate (CASNO.1810004-87-5) in a V-shaped reaction bottle, add 0.5ml of dichloromethane or dichloroethane, add 18 F-solution, irradiate with light at 200-400nm for 15 minutes, blow nitrogen to remove the solvent, add 100μl concentrated hydrochloric acid, react at 100℃ for 10 minutes, add saturated potassium carbonate to adjust the pH to 6-7, and purify by HPLC to prepare 18 F-mFBG. F-18 labeling chemical conversion rate of precursor and corresponding 18 The radiochemical purity of F-mFBG was determined by radio-HPLC. The results are shown in the following table. (ND: Not Detected)

[0062] Precursor <![CDATA[ 18 F-Chemical conversion rate]]> <![CDATA[ 18 F-mFBG radiochemical purity]]> 1 34.7,37.7,33.4,38.0 >95％ 3 2.1％,1.8％ ND 6 1.7％ ND 7 2.1％ ND

[0063] HPLC conditions for detecting the reaction solution: 70% MeCN: 30% KK (potassium phosphate buffer, pH: 8.0), flow rate: 1 ml / min.

[0064] Preparative HPLC conditions: 10% MeCN:90% H2O (0.1% trifluoroacetic acid), flow rate: 4 ml / min.

[0065] Post-purification detection 18 HPLC conditions of F-mFBG: 5% MeCN: 95% H2O (0.1% trifluoroacetic acid), flow rate: 1 ml / min, HPLC spectrum as shown Figure 1-Figure 2 shown.

[0066] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements fall within the scope of the present invention to be protected. The scope of the present invention to be protected is defined by the attached claims and their equivalents.

Claims

1. Preparation 18 The method of F-meta-fluorobenzylguanidine is characterized in that include 18 A phenol ether precursor compound corresponding to the core skeleton of F-mFBG and a synthesis method thereof, as well as a method for realizing F-18 labeling and preparation of mFBG using the precursor compound.

2. Preparation according to claim 1 18 The method of F-meta-fluorobenzylguanidine is characterized in that The phenol ether precursor compound has a structural formula as shown in Formula I: Among them, R1 and R2 are hydrogen or independently substituted with fluorine, chlorine, bromine, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, formate, formamide, alkyl, substituted alkyl, aryl, substituted aryl at any position of the benzene ring; R3, R4, R5, and R6 are independently hydrogen or any amino protecting group.

3. Preparation according to claim 2 18 The method of F-meta-fluorobenzylguanidine is characterized in that In the structural formula of the phenol ether precursor compound, R1 and R2 are hydrogen, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, formate, and formamide; R3, R4, R5, and R6 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, and dimethylformal.

4. Preparation according to claim 3 18 The method of F-meta-fluorobenzylguanidine is characterized in that In the structural formula of the phenol ether precursor compound, R1 and R2 are hydrogen, fluorine, chlorine, methyl, monofluoromethoxy, difluoromethoxy, or trifluoromethoxy; R3 is hydrogen or tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, tert-butyl, or dimethyl acetal; R4 is tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, benzyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl, phthaloyl, or p-toluene. R5 and R6 are independently hydrogen or tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, benzyloxycarbonyl, methoxycarbonyl, allyloxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, t-butyl, and dimethylformal.

5. Preparation according to claim 4 18 The method of F-meta-fluorobenzylguanidine is characterized in that In the structural formula of the phenol ether precursor compound, R1 and R2 are hydrogen; R3 is tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, dimethylformal, trityl, or tert-butyl; R4 is tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, trifluoroacetyl, or dimethylformal; R5 and R6 are independently hydrogen or tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, trifluoroacetyl, or dimethylformal, or R5 and R6 together with the protected amino group form a 6. Preparation according to claim 5 18 The method of F-meta-fluorobenzylguanidine is characterized in that The structure of the phenol ether precursor compound is characterized by:

7. The preparation according to claim 2 18 The method of F-meta-fluorobenzylguanidine is characterized in that The precursor compound is prepared by the following reaction to achieve F-18 labeling 18 F-Meta-Fluorobenzylguanidine: The photocatalyst used for the photocatalytic labeling reaction includes 9-striphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate, 9-striphenyl-3,6-di-tert-butyl-10-phenylacridine perchlorate, and riboflavin tetraacetate, preferably 9-striphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate; the solvent is dichloromethane or dichloroethane, and the protective group is removed after the F-18 labeling reaction and separated and purified to obtain 18 F-meta-Fluorobenzylguanidine.

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