Compound based on amino acid transporter mechanism of action and synthesis method and application thereof

Abstract

The application discloses a compound based on an amino acid transporter action mechanism and a synthesis method and application thereof. The application takes polyborate substituted phenylalanine derivatives as raw materials, and obtains radioiodine (radiohalogen) labeled phenylalanine analogues through hydrolysis and halogenation with metal halides. The phenylalanine analogues can be used as drugs for tumor treatment, radio-diagnostic drugs and drug combinations. The synthesis method of the phenylalanine analogues has few steps, simple operation, single reaction product, high yield and green environmental protection.

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and radiation medicine, and relates to a compound based on the mechanism of action of amino acid transporters, its synthesis method and application. Background Technology

[0002] Solute carrier (SLC) transporters are membrane transport proteins that transport nutrients, neurotransmitters, hormones, drugs, and toxins across the cell membrane. SLC transporters play a crucial role in physiological and pharmacological processes such as the absorption of small molecules, the absorption and release of nutrients and metabolites, the clearance and release of neurotransmitters, and the absorption, distribution, and excretion of drugs and other foreign substances.

[0003] L-amino acid transporters (LATs) are members of the solute carrier family 7 (SLC7). LAT1 (also known as SLC7A5) is a heteromeric amino acid transporter (HAT) that can take up not only a large number of neutral amino acids but also various drugs. LAT1 (or SLC7A5) and LAT2 (or SLC7A8) are two major isoforms of the SLC7 transporter gene family, discovered in 1998 and 1999, respectively. They are sodium-independent neutral amino acid transporters, active in renal epithelial cells, brain capillary endothelial cells, and normal and tumor neuroendocrine cells. Studies have shown that LAT1 is highly expressed in various human tumors, and its expression is significantly correlated with cell proliferation and angiogenesis.

[0004] As the role of the transporter LAT1 in drug preparation, drug interactions, drug efficacy, and toxicity becomes clearer, it is possible to use appropriately labeled substrates to target the uptake of the transporter for tissue-specific imaging in cancer patients.

[0005] Furthermore, effective radioactive tracers can be further developed into therapeutic probes by replacing the radioactive isotope with another radioactive isotope that emits stronger alpha or beta rays.

[0006] In 2001, Suominenl et al. from Helsinki University Hospital proposed introducing radioactive iodine at the 2-position of 4-boronic acid phenylalanine as an imaging technique. They synthesized a 2-nitrophenylboronic acid derivative from p-methylbromobenzene, then reduced it to an amino group and diazotized it to iodine. The process was lengthy and the yield was low. The literature has also reported that the desired compound has not been successfully synthesized.

[0007] In 2022, Luo Zhifu's team at the China Institute of Atomic Energy (CN115043864 A, CN115010739 A, CN115093438A) proposed using elemental iodine as a raw material. After converting elemental iodine to iodine chloride using hypochlorous acid and chloroite, it is then iodinated via an electrophilic reaction with BPA to obtain 2-iodo-BPA. However, elemental iodine is highly volatile, posing significant challenges to radiation protection when using radioactive elemental iodine. Clinically used I-125 is typically packaged in sealed containers, while commonly used I-131 exists as an aqueous sodium salt solution. Therefore, this method is limited in practical application. Summary of the Invention

[0008] The purpose of this invention is to provide a phenylalanine analog based on the amino acid transporter mechanism, its synthesis method, and its applications. The method involves using phenylalanine or substituted phenylalanine as a raw material, undergoing a nucleophilic reaction with an iodine source (potassium iodide or iodine) for iodination, further obtaining a boron-rich polyboron ester-substituted phenylalanine derivative, and finally, through hydrolysis and halogenation, obtaining a radiolabeled phenylalanine analog. This phenylalanine analog can be used as a tumor therapeutic drug, a radiodiagnostic drug, and drug combinations thereof. The synthesis method of this phenylalanine analog has few steps, is simple to operate, uses readily available raw materials, produces a single product, has a high yield, and utilizes an aqueous phase reaction, making it more environmentally friendly.

[0009] To achieve the above objectives, the present invention provides the following technical solution:

[0010] In a first aspect, the present invention provides a phenylalanine analogue with the structure shown in formula (III):

[0011]

[0012] In the formula:

[0013] R 1 It can be H, OH, CH3O, NH2 or Cl-C 12 Alkyl groups; preferably H, OH, CH3, CH3O or NH2;

[0014] m is 2 or 3;

[0015] n is 1 or 2;

[0016] * indicates an R-, S-, or (R- / S-) racemic mixture;

[0017] X is F, 18 F, Cl, Br, I 123 I, 124 I, 125 I, 131 I, At, 211 At or its isotopes, preferably I,123 I, 124 I, 125 I, 131 I, At or 211 At.

[0018] According to embodiments of the present invention, the phenylalanine analogue is one or more of the following compounds:

[0019]

[0020]

[0021] Secondly, the present invention further provides a method for synthesizing the phenylalanine analogue, comprising the following steps:

[0022] S1. Under acidic conditions, phenylalanine or substituted phenylalanine undergoes an iodination reaction with an iodine source to obtain iodophenylalanine compounds.

[0023] S2. Under acidic conditions, the iodophenylalanine compound reacts with an alcohol to form an ester, which further reacts with an acid anhydride or acyl chloride to form a protected iodophenylalanine derivative.

[0024] S3. In the presence of a metal catalyst and a base, the protected iodophenylalanine derivative undergoes a borate esterification reaction with a borate ester derivative to obtain a polyborate substituted phenylalanine derivative (the compound shown in Formula I).

[0025] S4. Under acidic conditions, the polyboronic ester substituted phenylalanine derivative is hydrolyzed to generate the compound shown in formula II;

[0026] S5. Under the action of a catalyst, the compound shown in Formula II undergoes a halogenation reaction with a metal halide to generate the phenylalanine analogue (the compound shown in Formula III).

[0027] In the above preparation method:

[0028] The structure of the iodophenylalanine compound is shown in Formula A:

[0029]

[0030] In formula A:

[0031] R 1 It can be H, OH, CH3O, NH2 or Cl-C 12 Alkyl groups; preferably H, OH, CH3, CH3O or NH2;

[0032] m is 2 or 3;

[0033] n is 1 or 2;

[0034] * indicates an R-, S-, or (R- / S-) racemic mixture.

[0035] The structure of the protected iodophenylalanine derivative is shown in Formula B:

[0036]

[0037] In formula B:

[0038] R 1 It can be H, OH, CH3O, NH2 or Cl-C 12 Alkyl groups; preferably H, OH, CH3, CH3O or NH2;

[0039] R 2 For tert-butyl;

[0040] R 3 R 4 Each is independently H and tert-butyl ester group;

[0041] m is 2 or 3;

[0042] n is 1 or 2;

[0043] * indicates an R-, S-, or (R- / S-) racemic mixture.

[0044] The structural formula of the polyboronic ester-substituted phenylalanine derivative is shown in Formula I:

[0045]

[0046] In Formula I:

[0047] R 1 It can be H, OH, CH3O, NH2 or Cl-C 12 Alkyl groups; preferably H, OH, CH3, CH3O or NH2;

[0048] R 2 For tert-butyl;

[0049] R 3 R 4 Each is independently H and tert-butyl ester group;

[0050] R 5 R 6 Each can be independently H, tert-butyl ester group, methoxy group, ethoxy group, propoxy group, butoxy group, or can form a five-membered ring or six-membered ring structure with B, such as pina ester (Pin);

[0051] m is 2 or 3;

[0052] n is 1 or 2;

[0053] * indicates an R-, S-, or (R- / S-) racemic mixture.

[0054] The structural formula of the compound shown in Formula II is as follows:

[0055]

[0056] In formula II,

[0057] R 1 It can be H, OH, CH3O, NH2 or Cl-C 12 Alkyl groups; preferably H, OH, CH3, CH3O or NH2;

[0058] m is 2 or 3;

[0059] n is 1 or 2;

[0060] * indicates an R-, S-, or (R- / S-) racemic mixture.

[0061] In step S1, the acid used in the acidic conditions is one or more of perchloric acid, hydrochloric acid, and dilute sulfuric acid.

[0062] In step S1, the iodine source is sodium iodide, potassium iodide, or iodine.

[0063] In step S1, the conditions for the iodination reaction are: a temperature of 50-100℃, preferably 75℃, and a reaction time of 12-36h, preferably 12h.

[0064] In step S2, the acid used in the acidic conditions is one or more of perchloric acid, hydrochloric acid, and dilute sulfuric acid.

[0065] In step S2, the alcohol is one or more of tert-butanol, ethanol, methanol, and tert-amyl alcohol.

[0066] In step S2, the conditions for reacting with alcohol to generate ester are: temperature of 50-60℃, preferably 55℃, and time of 11-13h, preferably 12h.

[0067] In step S2, the acid anhydride is di-tert-butyl carbonate and / or acetic anhydride.

[0068] In step S2, the acyl chloride is one or more of acetyl chloride, formyl chloride, and benzyloxyformyl chloride.

[0069] In step S2, the reaction conditions between the ester and the acid anhydride or acyl chloride are: a temperature of 0-20°C, preferably 15°C, and a time of 1-1.5 h, preferably 1 h.

[0070] In step S3, the metal catalyst is one or more of Pd(dppf)Cl2, Pd(dppp)Cl2, and Ni(dppp)Cl2.

[0071] In step S3, the alkali is one or more of potassium acetate, sodium acetate, potassium carbonate, and sodium carbonate.

[0072] In step S3, the borate ester derivative is B2Pin2 and / or HBPin.

[0073] In step S3, the conditions for the borate esterification reaction are: temperature of 85-120℃, preferably 90℃, and time of 1-1.5h, preferably 1h.

[0074] In step S3, according to an embodiment of the present invention, the polyboronic ester substituted phenylalanine derivative may be one of the following compounds:

[0075]

[0076]

[0077] In the above compounds, R = H or tert-butyl ester group.

[0078] In step S4, the oxidant used for hydrolysis is one or more selected from sodium periodate, potassium periodate, lithium periodate, rubidium periodate, beryllium periodate, magnesium periodate, calcium periodate, and barium periodate. The molar ratio of the polyboron ester-substituted phenylalanine derivative to the oxidant is 1:(0.1-20), preferably 1:(3-5), and more preferably 1:4.

[0079] In step S4, the acidic reagent used for hydrolysis is ammonium acetate. The molar ratio of the polyboronic ester-substituted phenylalanine derivative to the acidic reagent is 1:(0.1-20), preferably 1:(3-5), and more preferably 1:4.

[0080] In step S4, the solvent used for hydrolysis is one or more of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, water, acetonitrile, pyridine, triethylamine, 1,4-dioxane, tetrahydrofuran, and methyltetrahydrofuran.

[0081] In step S4, the hydrolysis conditions are: a temperature of 0-120℃, preferably 20-30℃, and more preferably 25℃.

[0082] In step S5, the catalyst is one or more of NBS, NIS, CuI, Cu2O, CuO, Cu(OTf)2 and Cu(OTf)2(Py)4; the mass ratio of the compound shown in Formula II to the catalyst is 1:(0.01-1), preferably 1:(0.2-0.5).

[0083] In step S5, the metal halide is NaI or Na 123I, Na 124 I, Na 125 I, Na 131 I, NaAt, Na 211 At, KF, K 18 F, one or more of potassium salt and cesium salt. The mass ratio of the compound shown in Formula II to the metal halide is 1:(0.00001-10), preferably 1:(0.1-1), and more preferably 1:0.5.

[0084] In step S5, the solvent used in the halogenation reaction is one or more of acetonitrile, water, pyridine, dimethylacetamide, dimethylformamide, and dimethyl sulfoxide, preferably water.

[0085] In step S5, the conditions for the halogenation reaction are: temperature of 0-150℃, such as 20-30℃, and time of 5-1200min, such as 5-15min.

[0086] Thirdly, the present invention further provides a pharmaceutical composition comprising the following components: the phenylalanine analogue and an additive.

[0087] The additives are one or more of the following: fructose, sorbitol, glucose, sialic acid, neuraminic acid, lentinan, hyaluronic acid, chondroitin sulfate, heparin, fructose 1,6-bisphosphate, and D-mannitol.

[0088] Fourthly, the present invention further provides the use of the phenylalanine analogue or the pharmaceutical composition in the preparation of a medicament or diagnostic reagent for treating cancer.

[0089] The beneficial effects achieved by this invention are as follows:

[0090] This invention uses phenylalanine or substituted phenylalanine and an iodine source as raw materials, and performs iodination and borate esterification reactions via nucleophilic reactions to obtain borate ester polysubstituted phenylalanine derivatives (compounds shown in Formula I). ​​Then, through hydrolysis and halogenation reactions, radioactive elements are obtained. 18 F, 123 I, 124 I, 125 I, 131 I, 211 At)-labeled phenylalanine analogues. This compound can be used as a drug for tumor treatment, a radiodiagnostic drug, and a drug combination. Its synthesis method has few steps, is simple to operate, uses readily available raw materials, produces a single reaction product, has a high yield, and uses an aqueous phase reaction, making it more environmentally friendly. Attached Figure Description

[0091] Figure 1 The HPLC chromatogram of compound 4 provided in Example 1.

[0092] Figure 2 The HPLC chromatogram of compound 5 provided in Example 1 is shown; wherein the retention peak of compound 5 is 4.56 min.

[0093] Figure 3 The radiometric TLC chromatogram of iodine (I-131)boronic acid phenyl-2-amino-propionic acid provided in Example 2.

[0094] Figure 4 Iodine (I-131) borate phenyl-2-amino-propionic acid (BIPA) and Na 131 Distribution map of organisms in region I. Detailed Implementation

[0095] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to the following embodiments.

[0096] Unless otherwise specified, all methods described herein are conventional methods.

[0097] Unless otherwise specified, all raw materials are available from publicly available commercial sources.

[0098] Example 1: Synthesis of phenyl-2-amino-propionic acid iodoboronic acid

[0099] The synthesis route is as follows:

[0100]

[0101] The synthesis steps are as follows:

[0102] (1) Synthesis of (S)-2,4-diiodophenylalanine (compound 1)

[0103] The steps are as follows:

[0104] Phenylalanine (8.25 g, 50.0 mmol, 1.0 eq), N-chlorosuccinimide (1.33 g, 10 mmol, 0.2 eq), trifluoromethanesulfonic acid (5 mL), and acetic acid (50 mL) were added to a 100 mL three-necked flask. Potassium iodide (16.6 g, 100.0 mmol, 1.0 eq) was added in portions while stirring. The mixture was then heated to 75 °C and reacted for 10 hours until the starting material disappeared as monitored by TLC. After removing acetic acid under reduced pressure, 30 mL of acetonitrile was added. The mixture was filtered and washed three times with 5 mL of acetonitrile. The solid was dissolved in water, and the pH was adjusted to 7 with sodium bicarbonate. The mixture was then filtered, washed three times with water, and recrystallized from the solid. After filtration and drying, 11.56 g of white needle-like crystals of compound 1 were obtained, with a yield of 55.6%.

[0105] (2) Synthesis of 2,4-diiodophenylalanine derivative (compound 2)

[0106] To a 100 mL three-necked flask, add (S)-2,4-diiodophenylalanine (compound 1) (5.0 g, 12.0 mmol, 1.0 eq), tert-butanol (25 mL), and 70% perchloric acid (1.73 g, 12.0 mmol, 1.0 eq). The mixture was stirred and gradually heated to 55 °C for 12 hours. After the reaction was complete, the mixture was cooled, concentrated under reduced pressure to remove tert-butanol, and then 25 mL of ethyl acetate and 25 mL of water were added. The mixture was separated, and the aqueous phase was extracted once with 25 mL of ethyl acetate. The combined organic phases were washed with 30 mL of saturated brine and concentrated under reduced pressure to obtain the intermediate ester.

[0107] The intermediate ester was added to a 100 mL three-necked flask, dissolved in 15 mL of tetrahydrofuran, and then 30 mL of water was added. The mixture was cooled to 10 °C with ice water while stirring. Sodium carbonate (2.1 g, 20 mmol, 6.0 eq) and di-tert-butyl carbonate (Boc)₂O (1.5 g, 20 mmol, 2.0 eq) were added. The reaction was carried out at 15 °C for 1 h. After the reaction was complete, 30 mL of ethyl acetate was added, and the mixture was stirred for 10 min. The mixture was separated into aqueous and organic phases. The aqueous phase was extracted once with ethyl acetate, and the combined organic phases were washed twice with saturated brine. The organic phase was dried and concentrated under reduced pressure, then separated by column chromatography (petroleum ether:ethyl acetate = 6:1) to give 1.6 g of tert-butyl 2-((tert-butoxycarbonyl)amino)-3-(2,4-diiodophenyl)propionate (compound 2), with a yield of 72%.

[0108] (3) Synthesis of 2,4-bispiconol ester phenylalanine derivative (compound 3)

[0109] A mixture of compound 2 (2.5 g, 5.0 mmol, 1 eq), B2Pin2 (6.6 g, 26.0 mmol, 5 eq), potassium acetate (2.05 g, 31 mmol, 4 eq), and Pd(dppf)Cl2 (0.38 g, 0.52 mmol, 0.1 eq) was degassed three times in 25 mL of dioxane solution. The mixture was then heated to 90 °C and stirred for 1 hour under N2 protection. The solid was removed by filtration, diluted with 10 mL of H2O, and extracted three times with 10 mL of EtOAc. The combined organic layers were washed with 50 mL of saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a pale yellow viscous solid (0.92 g, 58% yield), namely the 2,4-bispinalol ester phenylalanine derivative (compound 3).

[0110] (4) Synthesis of 3-(2,4-diboronic acid phenyl)-2-amino-propionic acid (compound 4)

[0111] Compound 3 (4.0 g, 7.0 mmol, 1.0 eq), sodium periodate (6.0 g, 28.0 mmol, 4.0 eq), ammonium acetate (2.2 g, 28.0 mmol, 4.0 eq), dimethyl sulfoxide (80 mL, 20 vol), and water (40 mL, 10 vol) were added to a 250 mL three-necked flask. The mixture was stirred and heated from 0 °C to 25 °C to carry out the hydrolysis reaction. The reaction was allowed to proceed overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 30 °C until no liquid was discharged. The mixture was extracted twice with dichloromethane (400 mL each time). The organic phases were combined, washed with water (60 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 2.5 g of foamy solid.

[0112] Add 2.5 g of foamy solid, 10 mL of dichloromethane (4 vol), and 4 mL of trifluoroacetic acid (2 vol) to a 100 mL three-necked flask. Start stirring and heat the system to 20 °C. React overnight. Concentrate under reduced pressure at 30 °C. Then add 30 mL of dichloromethane and evaporate to dryness. Repeat this process three times. Slowly add 60 mL of n-hexane and stir for 30 min. Filter the mixture. Wash the filter cake with 12 mL of n-hexane and dry it under vacuum. Dry the filter cake under reduced pressure at 30 °C to obtain compound 4 (1.6 g, yield 95%).

[0113] The HPLC chromatogram of compound 4 is as follows: Figure 1 As shown, I H NMR(DMSO-d6,δppm):3.17(m,1H),3.42(m,1H),4.18(m,1H),4.20(s,4H),7.20(d,1H),7.33(s,1H),7.52(d,1H),8.71(d,2H),12.1(bs,1H).

[0114] (5) Synthesis of 3-(phenyl iodoboronic acid)-2-amino-propionic acid (compound 5)

[0115] At room temperature, an aqueous solution of NaI (1 mg) and oxidant NBS (1 mg) was added to an aqueous solution of compound 4 (2 mg), and the mixture was stirred at room temperature for 10 minutes. The resulting reaction solution was separated by high performance liquid chromatography with a mobile phase of 0.1% HOAc / 90% acetonitrile (phase A) to obtain the target product compound 5.

[0116] The HPLC chromatogram of compound 5 is as follows: Figure 2 As shown, the retention peak of compound 5 is at 4.56 min. IH NMR(DMSO-d6,δppm):3.18(m,1H),3.42(m,1H),4.15(m,1H),4.19(s,2H),7.19(d,1H),7.30(s,1H),7.49(d,1H),8.72(d,2H),12.2(bs,1H).

[0117] Example 2: Synthesis of iodinated (I-131)boronic acid phenyl-2-amino-propionic acid

[0118] (1)-(4) Same as Example 1.

[0119] (5) Synthesis of iodine (I-131)boronic acid phenyl-2-amino-propionic acid

[0120] At room temperature, an aqueous solution of NBS (0.2 mg) was added to 300 μL of an aqueous solution of compound 4 (1 mg), followed by the addition of Na. 131 I (0.6 mCi) was stirred at room temperature for 10 minutes to obtain iodo(I-131)boronic acid phenyl-2-amino-propionic acid. Since the amount of the prepared compound was very small, no further purification was required.

[0121] The radiometric TLC analysis chromatogram of the obtained iodine (I-131) borate phenyl-2-amino-propionic acid is shown below. Figure 3 As shown, the radioactive TLC spot analysis showed an Rf value of 0.59.

[0122] The above method can also be used to obtain the following compounds.

[0123] Table 1. List of some raw materials and synthetic products provided by this invention.

[0124]

[0125]

[0126] Pharmacokinetic analysis

[0127] The 115 μCi of iodine (I-131) borate phenyl-2-amino-propionic acid synthesized in Example 2 was injected intraperitoneally into normal mice. One hour later, the mice were sacrificed, and their hearts, livers, spleens, lungs, and kidneys were taken and weighed. Then, gamma counters were used to measure the gamma counts to obtain the biodistribution of the iodine drug, which was generally calculated as %ID / g.

[0128] The calculation formula is as follows:

[0129] %ID / g = (Radioactivity count of organ / Radioactivity count of injected drug) / Organ mass.

[0130] Table 2. Biodistribution of iodine (I-131) borate phenyl-2-amino-propionic acid

[0131]

[0132]

[0133] Take Na 131 As a control, normal mice were injected with 130 μCi of Na. 131 I. After 1 hour, the mice were sacrificed, and tissues such as heart, liver, spleen, lungs, and kidneys were collected, weighed, and gamma counts were measured.

[0134] Table 3 Na 131 Biodistribution of I

[0135] Heart 0.1282 19294 0.031289 lung 0.135 29556 0.045516 liver 0.6145 62309 0.021080 spleen 0.0999 15374 0.031994 kidney 0.1276 34104 0.055566

[0136] Iodine (I-131) borate phenyl-2-amino-propionic acid and Na 131 The comparison results of I are as follows Figure 4 As shown, one hour after injection, the concentrations of iodine (I-131)boronic acid phenyl-2-amino-propionic acid in the heart, liver, spleen, lungs, and kidneys were higher than those in sodium. 131 The concentration of I indicates that it can be used to analyze drug uptake in different tissues and organs, as well as for possible imaging studies.

[0137] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A method for synthesizing a phenylalanine analogue, comprising the following steps: S1. Under acidic conditions, phenylalanine or substituted phenylalanine undergoes an iodination reaction with an iodine source to obtain iodophenylalanine compounds. S2. Under acidic conditions, the iodophenylalanine compound reacts with an alcohol to form an ester, which further reacts with an acid anhydride or acyl chloride to form a protected iodophenylalanine derivative. S3. In the presence of a metal catalyst and a base, the protected iodophenylalanine derivative undergoes a borate esterification reaction with a borate ester derivative to obtain a polyborate substituted phenylalanine derivative. S4. Under acidic conditions, the polyboronic ester substituted phenylalanine derivative is hydrolyzed to generate the compound shown in formula II; S5. Under the action of a catalyst, the compound shown in Formula II undergoes a halogenation reaction with a metal halide to generate the phenylalanine analogue. In step S5, the catalyst is NBS; in: The iodophenylalanine compound is any one of the following: The protected iodophenylalanine derivative is any one of the following: The polyboronic ester-substituted phenylalanine derivative is one of the following compounds: ； The compound represented by Formula II is any one of the following: The phenylalanine analogue is any one of the following: ； In step S5, the mass ratio of the compound shown in Formula II to the catalyst is 1:(0.01-1). In step S5, the metal halide is NaI or Na 123 I, Na 124 I, Na 125 I, Na 131 I, NaAt and Na 211 At, one or more of the following; The mass ratio of the compound shown in Formula II to the metal halide is 1:(0.00001-10). The solvent used in the halogenation reaction is one or more of acetonitrile, water, pyridine, dimethylacetamide, dimethylformamide, and dimethyl sulfoxide; In step S5, the conditions for the halogenation reaction are: temperature 0-150℃ and time 5-1200 min.

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