An amino acid-BSH targeted hybrid compound and its preparation method and application

Abstract

The present invention discloses an amino acid-BSH targeted hybrid compound and a preparation method thereof, as well as the use of the targeted hybrid compound in the preparation of relevant cancer therapeutic drugs in the process of treating cancer using a boron neutron capture method. The structure of the amino acid-BSH targeted hybrid compound is shown in Formula I. The amino acid-BSH targeted hybrid compound of the present invention has better boron uptake and T / N ratio in the corresponding tumor than the positive control drug borocarbazone; its permeability to cells is better than borocarbazone. The preparation method of the amino acid-BSH targeted hybrid compound of the present invention has the characteristics of mild reaction conditions, simple experimental steps, high yield, high product purity, economy and practicality.

Description

Technical Field

[0001] The present invention relates to the fields of pharmaceutical chemistry and radiation medicine, and in particular to an amino acid-BSH targeting hybrid compound and a preparation method and application thereof. Background Art

[0002] Cancer is a large class of diseases characterized by abnormal cell proliferation and metastasis. Among urban residents, cancer has become the leading cause of death. Although scientists from all over the world have conducted in-depth research on how to overcome cancer, a world problem, from many disciplines over the years and proposed a variety of therapies, these therapies have certain effects on specific subjects, but the efficacy is not satisfactory and there is still a long way to go before a radical cure. Therefore, the research on cancer treatment drugs and technologies is still a hot spot and difficulty in today's medical field.

[0003] Boron neutron capture therapy (BNCT) for cancer treatment is a new radiotherapy technology. It is a binary therapy based on nuclear capture and fission reaction. Compared with traditional radiotherapy and chemotherapy, it has the advantages of low side effects, high selectivity and high efficiency. However, this technology requires both high-quality neutron beams and highly targeted boron-containing drugs. The two are closely coordinated and indispensable. Only when both conditions are met can the tumor be targeted and killed at the cellular level. At present, the development of BNCT neutron beam equipment has made great progress (Science Bulletin 2022, 67(14), 1471-1478); in terms of boron drugs, only disodium thiododecaboron (BSH) and L-dihydroxyboronophenylalanine (BPA) are approved by the FDA for clinical use. Both have the problem of insufficient tumor targeting. For BSH, it also has problems such as inability to penetrate the blood-brain barrier, low tumor uptake and retention, and certain toxic side effects. It can be seen that clinically practical highly targeted boron drugs still cannot keep up with the requirements of BNCT treatment.

[0004] Studies have found that L-amino acid transporter 1 (LAT1) can transport neutral amino acids such as leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, methionine and histidine. LAT1 is highly expressed in human tumor tissues. Boron-containing compounds can be designed as substrates that mimic amino acids and selectively delivered to target cells through LAT1 mediation, thereby increasing the accumulation and selectivity of boron-containing compounds in tumor cells and improving their ability to penetrate the blood-brain barrier (BBB). Summary of the invention

[0005] In order to improve the tumor targeting, BBB penetration and active absorption ability of disodium dodecaboron thiolate (BSH), the technical problem solved by the present invention is to provide an amino acid-BSH targeting hybrid compound.

[0006] The technical problem solved by the present invention is also to provide the use of the above-mentioned targeted hybrid compound in the preparation of relevant cancer treatment drugs during the process of treating cancer using the boron neutron capture method.

[0007] The above technical problems solved by the present invention are achieved through the following technical solutions:

[0008] An amino acid-BSH targeting hybrid compound, the structure of which is shown in Formula I,

[0009]

[0010] Where X is CHMe 2 , CH 2 CH 2 、CH(CH 3 )CH 2 CH 3 , CH 2 CH 2 SMe, Bn, CH 2 (3-Indoyl), CH 2 [4-(OH)Ph], CH 2 [3,4-bis(OH)Ph], CH 2 (4-Imidazolyl); the carbon configuration marked by * can be R- or S-; Y can be O or NH; B is 10 B or natural boron ( 10 B / 11 B about 1 / 4); SNaB 12 H 11 The structure is as follows:

[0011]

[0012] Preferably, the amino acid-BSH targeting hybrid compound includes the following specific compounds:

[0013]

[0014]

[0015] The method for preparing the amino acid-BSH targeting hybrid compound, when Y=O, comprises the following steps:

[0016] Preparation of (O-1) 2-(2-(2-hydroxyethoxy)ethoxy)ethyl active ester (TrG Es): Weigh triethylene glycol and dissolve it in dry redistilled dichloromethane (DCM), add a stirrer, add an appropriate amount of organic base under ice bath, add acylating agent in batches, stir and react at room temperature for about 30 minutes, and continue to react at room temperature for 12 hours. Add an appropriate amount of DCM, wash with water, acid wash, dry, and concentrate under reduced pressure.

[0017] The synthetic route is as follows:

[0018]

[0019] In the above steps, the molar ratio of triethylene glycol to the organic base is 1:1.1-1.5; the molar ratio of triethylene glycol to the acylating agent is 1:1.1-1.5.

[0020] The organic base is any one of triethylamine, trimethylamine and diisopropylethylamine; the acylating agent is any one of p-toluenesulfonyl chloride, methanesulfonyl chloride and trifluoromethanesulfonyl chloride.

[0021] (O-2) Preparation of N-tert-butyloxycarbonyl amino acid ester bridged active ester (N-Boc-AA-O-TrG Es): Weigh N-Boc amino acid and dissolve it in an appropriate amount of DCM. Place the reaction bottle in an ice bath for 5 minutes, add the condensing agent and 4-dimethylaminopyridine (DMAP) in turn, keep stirring in the ice bath for 10 minutes, then add TrG Es. After the addition is completed, continue to react in an ice bath for 30 minutes, and then keep the reaction at room temperature for 12 hours. After the reaction is completed, add an appropriate amount of DCM, wash the DCM layer with water and 1N HCl in turn, dry, and concentrate to obtain the residue, which is purified by silica gel column chromatography and concentrated to obtain the target product.

[0022] The synthetic route is as follows:

[0023]

[0024] In the above steps, the molar ratio of N-Boc amino acid to condensing agent is 1:1.1-1.5; the molar ratio of N-Boc amino acid to DMAP is 1:0.1-0.5; and the molar ratio of N-Boc amino acid to TrG Es is 1:1.1-1.5.

[0025] The condensing agent is any one of 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), ethyl chloroformate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), N,N'-diisopropylcarbodiimide (DIC), and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (PyBOP).

[0026] (O-3) Preparation of N-tert-butyloxycarbonyl amino acid ester bridged bromine (N-Boc-AA-O-TrG-Br): Weigh the compound N-Boc-AA-O-TrG Es and dissolve it in an appropriate amount of acetone, add lithium bromide, and place the reactor in an oil bath at an appropriate temperature to heat and react for 2 to 10 hours. After the reaction is completed, evaporate the solvent, add an appropriate amount of DCM, wash with water, dry, and separate and purify by column chromatography.

[0027] The synthesis steps are as follows:

[0028]

[0029] In the above steps, the molar ratio of N-Boc-AA-O-TrG Es to lithium bromide is 1:1.1-1.5; the reaction temperature is 40-100°C, preferably 58°C.

[0030] (O-4) Preparation of N-tert-butyloxycarbonyl amino acid ester bridged borocarb (N-Boc-AA-O-TrG-BSH): Weigh the compound N-Boc-AA-O-TrG Br and borocarb sodium and dissolve them in an appropriate amount of dry acetonitrile, add inorganic base and potassium iodide under stirring, and place the reaction system in an oil bath and heat under reflux for 5 to 10 hours. After the reaction is completed, the solvent is removed by rotary evaporation, and the residue is separated and purified by rapid column chromatography.

[0031] The synthetic route is as follows:

[0032]

[0033] In the above steps, the molar ratio of N-Boc-AA-O-TrG-Br to sodium borocarb is 1.1-1.5:1; the molar ratio of N-Boc-AA-O-TrG-Br to inorganic base is 1:2.0-5.0; and the molar ratio of N-Boc-AA-O-TrG-Br to potassium iodide is 1:2.0-5.0.

[0034] The inorganic base is lithium carbonate, cesium carbonate, potassium carbonate, preferably cesium carbonate.

[0035] (O-5) Preparation of amino acid ester bridged borocard (AA-O-BSH): Weigh the compound N-Boc-AA-O-TrG-BSH and dissolve it in dry DCM, place it in an ice bath and cool it for 5 minutes, add acid while stirring, then warm it to room temperature and continue to react for 1 to 5 hours. TLC detection shows that the reaction is completely converted (developing solvent: DCM / MeOH=1 / 1). Saturated sodium bicarbonate is used to adjust the pH of the reaction system to weak alkalinity, and the solvent is removed by rotary evaporation. The residue is separated by column chromatography and freeze-dried to obtain the product.

[0036] The synthetic route is as follows:

[0037]

[0038] In the above steps, the molar ratio of N-Boc-AA-O-TrG-BSH to the acid is 1.0:100-250; the acid is any one of trifluoroacetic acid (TFA) and hydrochloric acid / DCM solution.

[0039] The method for preparing the amino acid-BSH targeted hybrid compound, when Y=NH, comprises the following steps:

[0040] (N-1) Preparation of N-tert-butyloxycarbonyl amino acid amide bridged alcohol (N-Boc-AA-N-TrG-OH): Weigh N-Boc amino acid and dissolve it in an appropriate amount of DCM. Place the reaction bottle in an ice bath for 5 minutes, add the condensing agent and organic base in turn, keep stirring in the ice bath for 10 minutes, then add 2-(2-(2-aminoethoxy)ethoxy)ethanol. After the addition is completed, continue to react in an ice bath for 30 minutes, and then keep the reaction at room temperature for 12 hours. After the reaction is completed, add an appropriate amount of DCM, wash the DCM layer with water and 1N HCl in turn, dry, and concentrate to obtain the residue, which is purified by silica gel column chromatography to obtain the target product.

[0041] The synthetic route is as follows:

[0042]

[0043] In the above steps, the molar ratio of N-Boc amino acid to condensing agent is 1:1.1-1.5; the molar ratio of N-Boc amino acid to organic base is 1:2.0-5.0; the molar ratio of N-Boc amino acid to 2-(2-(2-aminoethoxy)ethoxy)ethanol is 1:1.1-1.5.

[0044] The condensing agent is the same as that in step (O-2); the organic base is any one of diisopropylethylamine (DIPEA), triethylamine, and 2,2,6,6-tetramethylpiperidine.

[0045] (N-2) Preparation of N-tert-butyloxycarbonyl amino acid amide bridged active ester (N-Boc-AA-N-TrG Es): Replace triethylene glycol with N-tert-butyloxycarbonyl amino acid amide bridged alcohol and prepare according to the method described in step (O-1). The synthetic route is as follows:

[0046]

[0047] (N-3) Preparation of N-tert-butoxycarbonyl amino acid amide bridged bromide (N-Boc-AA-N-TrG-Br): Replace the N-tert-butoxycarbonyl amino acid ester bridged active ester with the N-tert-butoxycarbonyl amino acid amide bridged active ester and prepare it according to the method described in step (O-3). The synthetic route is as follows:

[0048]

[0049] (N-4) Preparation of N-tert-butyloxycarbonyl amino acid amide bridged borocarbyl (N-Boc-AA-N-TrG-BSH): Replace the N-tert-butyloxycarbonyl amino acid ester bridged bromide with N-tert-butyloxycarbonyl amino acid amide bridged bromide and prepare according to the method described in step (O-4). The synthetic route is as follows:

[0050]

[0051] (N-5) Preparation of amino acid amide bridged boron card (AA-N-BSH): Replace the N-tert-butyloxycarbonyl amino acid ester bridged boron card with the N-tert-butyloxycarbonyl amino acid amide bridged boron card and prepare it according to the method described in step (O-5). The synthetic route is as follows:

[0052]

[0053] The present invention uses the MTT method to detect the cytotoxicity of a series of amino acid-BSH targeting hybrid compounds on human umbilical vein endothelial cells (HUVEC), human normal liver cells (LO2) and human liver cancer cells (HepG2), and finds that the compounds have no toxicity within a concentration range of 500 μM.

[0054] The present invention uses ICP-MS to detect the uptake of a series of amino acid-BSH targeted hybrid compounds in human umbilical vein endothelial cells (HUVEC), human liver cancer cells (HepG2), human breast cancer cells (MDA-MB-231) and human glioma cells (U87) as well as the T / N ratio (boron uptake of tumor cells / boron uptake of normal cells). The results show that the boron uptake of the series of amino acid-BSH targeted hybrid compounds in the cells investigated is greater than 10 9 B / cells, all fall within 10 11 B / cell range, T / N>3; compared with BSH, for different tumor cells, the amino acid-BSH targeting hybrids with corresponding structures showed superior boron uptake properties than BSH.

[0055] The present invention uses a shake flask method combined with HPLC technology to detect the lipophilicity and hydrophilicity coefficients of a series of amino acid-BSH targeted hybrid compounds. The results show that all amino acid-BSH targeted hybrid compounds show lipophilicity and hydrophilicity characteristics that are superior to BSH, and they optimize the disadvantage of BSH being too hydrophilic.

[0056] Compared with the prior art, the present invention has the following beneficial effects:

[0057] (1) The compound of formula (I) and its synthesis method described in the present invention are reported for the first time. The synthesis method of the present invention has the characteristics of mild reaction conditions, simple experimental steps, high yield, high product purity, economical and practical;

[0058] (2) The amino acid-BSH targeting hybrid compounds of the present invention have the property of targeting LAT1. Compared with BSH, they have a higher T / N ratio and boron loading capacity in tumor cells;

[0059] (3) Compared with BSH, the amino acid-BSH targeting hybrid compound of the present invention has better lipophilic and hydrophilic characteristics. DETAILED DESCRIPTION

[0060] The present invention is further explained below with reference to the examples, but the examples do not limit the present invention in any form.

[0061] Example 1. Preparation of Amino Acid Ester Bridged Boron Card (AA-O-BSH)

[0062] 1.1. Preparation of Valine Ester-bridged Boron Card (Val-O-BSH)

[0063] Synthesized in 5 steps.

[0064] 1.1.1. Preparation of 2-(2-(2-hydroxyethoxy)ethoxy)ethyl p-toluenesulfonate: Weigh 1.5 g (10.0 mmol) of triethylene glycol into a 100 ml round-bottom flask, place a magnetic bar, and add 5 ml of redistilled dichloromethane under stirring. Place the reaction flask in an ice bath and stir for 5 minutes, then add 1.2 g (11.8 mmol) of triethylamine (TEA), followed by adding 2.25 g (11.8 mmol) of p-toluenesulfonyl chloride (TsCl) in three portions over 6 minutes. Continue stirring at room temperature for 30 minutes, then warm the reaction system to room temperature and continue the reaction for 12 hours. TLC detection shows that the reaction is completely converted (developing solvent: PE / EA=3 / 1, R f =0.3). 50 ml of dichloromethane was added to the reaction system for dilution, and the mixture was washed with purified water (3×60 ml) and 1 mol / L HCl aqueous solution (3×60 ml) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure (0.1 MPa) at 60°C to obtain 2.41 g of a colorless transparent liquid with a yield of 79.1%. 1 H NMR (400 MHz, CDCl 3 )δ7.75(d,J=6.6Hz,2H),7.31(d,J=7.2Hz,2H),4.14(m,2H),3.66(m,4H),3.55(m,4H),3.52(m,2H),2.97(s,1H),2.40(s,3H).

[0065] 1.1.2. Preparation of N-tert-butyloxycarbonyl valine ester bridged toluenesulfonate (N-Boc-Val-O-TrG Ts): Weigh 0.65 g (3.0 mmol) of N-Boc-L-valine in a 50 ml round-bottom flask, add 20 ml of dry dichloromethane, put in a magnetic bar, and stir to dissolve the substrate. Place the reaction flask in an ice bath for 5 minutes, add EDCI (0.69 g, 3.6 mmol) and DMAP (0.11 g, 0.9 mmol) in sequence, maintain ice bath stirring for 10 minutes, then add 2-(2-(2-hydroxyethoxy)ethoxy)ethyl p-toluenesulfonate (1.0 g, 3.0 mmol), continue to react in an ice bath for 30 minutes after addition, then transfer to room temperature for 12 hours. TLC detection shows that the reaction is completely converted (developing solvent: PE / EA = 1 / 3 to 1 / 1). The reaction solution was washed with purified water (3×20 ml) and 1 mol / L HCl solution (3×20 ml) in sequence. The organic phases were combined, dried, and concentrated to obtain the residue, which was purified by silica gel column chromatography (200-300 mesh, eluent: PE / EA=3 / 1 to 1 / 1) to obtain 1.25 g of the target product with a yield of 82.8%. 1 H NMR (400 MHz, CDCl 3 )δ7.79(d,J=8.3Hz,2H),7.34(d,J=8.1Hz,2H),5.06(d,J=8.8Hz,1H),4.29(t,J=4.9Hz,1H),4.25(m,2H),4.18–4 .13(m,2H),3.71–3.63(m,4H),3.57(m,4H),2.44(s,3H),2.13(td,J=12.7,6.4Hz,1H),1.44(s,9H),0.92(m,6H).

[0066] 1.1.3. Preparation of N-tert-butyloxycarbonyl valine ester bridged bromide (N-Boc-Val-O-TrG Br): Weigh 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate in a 50 ml round-bottom flask, add a magnetic stirrer and acetonitrile (10 ml), and add 0.87 g (10.0 mmol) of LiBr under stirring. Then, place the reaction system in a 58°C oil bath and heat and stir to react for 6 hours, followed by TLC, until the reaction is complete. Then, the solvent is evaporated under reduced pressure, 20 ml of dichloromethane is added to the residue, washed with purified water (3×20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 766.9 mg of a colorless liquid with a yield of 93.0%. 1 H NMR (400 MHz, CDCl 3)δ5.05(d,J=8.6Hz,1H),4.46(s,1H),4.29(m,2H),3.81(t,J=6.3Hz,2H),3.72(t,J=4.9Hz,2H),3.66 (s,4H),3.48(t,J=6.3Hz,2H),2.15(m,1H),1.45(s,9H),0.97(d,J=6.9Hz,3H),0.90(d,J=6.9Hz,3H); 13 C NMR (101 MHz, CDCl 3 )δ:172.26,155.84,79.75,71.20,70.54,70.33,69.10,64.01,58.51,31.37,30.20,28.32,18.97.

[0067] 1.1.4. Preparation of N-tert-butyloxycarbonyl valine ester bridged borosulfate (N-Boc-Val-O-TrG BSH): Weigh 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valine ester bridged bromine, 53.5 mg (0.29 mmol) of borosulfate ( 10 BSH) was placed in a 100 ml round-bottom three-necked flask, a magnetic bar was placed, 15 ml of dry acetonitrile was added, and 244.0 mg (0.75 mmol) of cesium carbonate and 50.0 mg (0.3 mmol) of potassium iodide were added under stirring. The reaction system was placed in an oil bath and heated under reflux for 12 hours. HPLC detected that the reaction substrate conversion was more than half and new products were generated. The heating was stopped, the reaction solution was cooled to room temperature, 5 g of silica gel was directly added to mix the sample, and the product was separated and purified by rapid column chromatography (200-300 mesh, eluent: DCM / MeOH=20 / 1 to 10 / 1) to obtain 75.3 mg of the product with a yield of 57.0%.

[0068] 1.1.5. Preparation of valine ester bridged borosulfate (Val-O-BSH): Weigh 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate in a 50 ml round-bottom flask, add 10 ml of dry dichloromethane, stir to dissolve, place the system in an ice bath and stir for 5 minutes, add 2.0 ml of trifluoroacetic acid (TFA), and slowly warm to room temperature, continue stirring to react for 2 hours, and track the reaction by TLC detection (developing solvent: DCM / MeOH=1 / 1). Adjust the pH of the reaction system to neutral with saturated sodium bicarbonate, concentrate and evaporate the solvent, separate the residue by column chromatography, and freeze-dry to obtain 45.0 mg of the product, with a yield of 76.1%. 1 H NMR (400 MHz, DMSO-d 6)δ8.61(s,1H),4.44-4.31(m,1H),4.24-4.11(m,2H),4.02-3.98(m,2H),3.79-3.69(m,3H),3.69-3.61(m,3H),3.58-3.45 (m,4H),3.44-3.34(m,1H),3.25-3.02(m,2H),2.23-2.09(m,1H),1.83-1.02(m,5H),1.01-0.90(m,6H),0.87-0.47(m,1H); 13 C NMR (101 MHz, DMSO-d 6 )δ174.54,116.12,70.06,69.78,68.46,57.54,51.56,48.85,45.38,29.85,18.52. All data prove that the compound is L-valine (2-(2-(2-(sodium dodecaboryl mercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (Val-O-BSH), and its structural formula is as follows:

[0069]

[0070] 1.2. Preparation of Leucine Ester-bridged Boron Card (Leu-O-BSH)

[0071] Synthesized in 5 steps.

[0072] 1.2.1. The experimental steps are the same as 1.1.1.

[0073] 1.2.2. Preparation of N-tert-butyloxycarbonylleucine ester bridged p-toluenesulfonate (N-Boc-Leu-O-TrG Ts): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.69 g (3.0 mmol) of N-Boc-L-leucine and prepared according to the experimental procedure 1.1.2. After separation and purification, 1.31 g of colorless liquid was obtained with a yield of 84.4%. 1 HNMR (400MHz, CDCl 3)δ7.80(d,J=8.2Hz,2H),7.35(d,J=8.2Hz,2H),4.96(d,J=8.2Hz,1H),4.3 3-4.29(m,1H),4.26(dd,J=9.0,4.4Hz,2H),4.20-4.13(m,2H),3.69(dt,J =14.7,5.0Hz,4H),3.58(m,4H),2.45(s,3H),1.70(dt,J=19.4,6.5Hz,1H) ,1.65-1.54(m,1H),1.54-1.47(m,1H),1.44(s,9H),0.93(d,J=6.6Hz,6H).

[0074] 1.2.3. Preparation of N-tert-butyloxycarbonylleucine ester bridged bromide (N-Boc-Leu-O-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonylvaline ester bridged p-toluenesulfonate was replaced with 1.04 g (2.0 mmol) of N-tert-butyloxycarbonylleucine ester bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 738.4 mg of colorless liquid was obtained by separation and purification, with a yield of 86.6%. 1 H NMR (400 MHz, CDCl 3 )δ4.95(s,1H),4.26(m,2H),3.79(s,1H),3.74-3.54(m,8H),3.45(m,2H), 1.69(m,1H),1.58(m,1H),1.48(m,1H),1.42(s,9H),0.92(d,J=4.7Hz,6H); 13 CNMR (101MHz, CDCl 3 )δ174.28,155.16,79.69,71.19,70.48,68.97,64.08,61.66,51.93,41.75,30.37,28.42,24.71,22.63.

[0075] 1.2.4. Preparation of N-tert-butyloxycarbonylleucine ester bridged borocalcin sodium (N-Boc-Leu-O-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromine was replaced with 106.6 mg (0.25 mmol) of N-tert-butyloxycarbonylleucine ester bridged bromine, prepared according to the experimental procedure 1.1.4. 61 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 51.7%.

[0076] 1.2.5. Preparation of leucine ester bridged borosulfate (Leu-O-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonylvaline ester bridged borosulfate was replaced with 75.9 mg (0.14 mmol) of N-tert-butyloxycarbonylleucine ester bridged borosulfate according to the experimental procedure 1.1.5. 35.0 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 56.5%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.40(s,2H),4.49-4.11(m,2H),3.96(s,1H),3.75(s,2H),3.65(s,2H),3.59-3.36 (m,6H),3.26-3.04(m,2H),1.81-1.68(m,1H),1.66-1.53(m,2H),1.50-0.32(m,15H); 13 C NMR (101 MHz, DMSO-d 6 )δ170.47,72.80,70.28,68.63,66.52,65.41,60.66,51.06,42.07,24.18,22.72,22.47. All data confirmed that the compound was L-leucine (2-(2-(2-(sodium dodecaborylmercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (Leu-O-BSH), and its structure is as follows:

[0077]

[0078]

[0079] 1.3. Preparation of D-leucine ester-bridged borocard (D-Leu-O-BSH)

[0080] Synthesized in 5 steps.

[0081] 1.3.1. The experimental steps are the same as 1.1.1.

[0082] 1.3.2. Preparation of N-tert-butyloxycarbonyl D-leucine ester bridged p-toluenesulfonate (N-Boc-D-Leu-O-TrGTs): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.69 g (3.0 mmol) of N-Boc-D-leucine and prepared according to the experimental procedure 1.1.2. After separation and purification, 1.32 g of colorless liquid was obtained with a yield of 84.7%. 1 H NMR (400 MHz, CDCl 3)δ7.80(d,J=8.2Hz,2H),7.35(d,J=8.2Hz,2H),4.96(d,J=8.2Hz,1H),4.3 3-4.29(m,1H),4.26(dd,J=9.0,4.4Hz,2H),4.20-4.13(m,2H),3.69(dt,J =14.7,5.0Hz,4H),3.58(m,4H),2.45(s,3H),1.70(dt,J=19.4,6.5Hz,1H) ,1.65-1.54(m,1H),1.54-1.47(m,1H),1.44(s,9H),0.93(d,J=6.6Hz,6H).

[0083] 1.3.3. Preparation of N-tert-butyloxycarbonyl D-leucine ester bridged bromide (N-Boc-D-Leu-O-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.04 g (2.0 mmol) of N-tert-butyloxycarbonyl D-leucine ester bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 738.6 mg of colorless liquid was obtained by separation and purification, with a yield of 86.7%. 1 H NMR (400 MHz, CDCl 3 )δ4.95(s,1H),4.26(m,2H),3.79(s,1H),3.74-3.54(m,8H),3.45(m,2H), 1.69(m,1H),1.58(m,1H),1.48(m,1H),1.42(s,9H),0.92(d,J=4.7Hz,6H); 13 C NMR (101 MHz, CDCl 3 )δ174.28,155.16,79.69,71.19,70.48,68.97,64.08,61.66,51.93,41.75,30.37,28.42,24.71,22.63.

[0084] 1.3.4. Preparation of N-tert-butyloxycarbonyl D-leucine ester bridged borosulfate (N-Boc-D-Leu-O-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valine ester bridged bromide was replaced with 106.6 mg (0.25 mmol) of N-tert-butyloxycarbonyl leucine ester bridged bromide, prepared according to the experimental procedure 1.1.4. 61 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 51.7%.

[0085] 1.3.5. Preparation of D-leucine ester bridged borosulfate (Leu-O-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate was replaced with 75.9 mg (0.14 mmol) of N-tert-butyloxycarbonyl D-leucine ester bridged borosulfate according to the experimental procedure 1.1.5. 35.2 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 56.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.40(s,2H),4.49-4.11(m,2H),3.96(s,1H),3.75(s,2H),3.65(s,2H),3.59-3.36 (m,6H),3.26-3.04(m,2H),1.81-1.68(m,1H),1.66-1.53(m,2H),1.50-0.32(m,15H); 13 C NMR (101 MHz, DMSO-d 6 )δ170.47,72.80,70.28,68.63,66.52,65.41,60.66,51.06,42.07,24.18,22.72,22.47. All data confirmed that the compound was D-leucine (2-(2-(2-(sodium dodecaborylmercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (D-Leu-O-BSH), and its structure is as follows:

[0086]

[0087] 1.4. Preparation of Isoleucine Ester-bridged Boron Card (Ile-O-BSH)

[0088] Synthesized in 5 steps.

[0089] 1.4.1. The experimental steps are the same as 1.1.1.

[0090] 1.4.2. Preparation of N-tert-butyloxycarbonyl isoleucine ester bridged p-toluenesulfonate (N-Boc-Ile-O-TrG Ts): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.69 g (3.0 mmol) of N-Boc-L-isoleucine and prepared according to the experimental procedure 1.1.2. After separation and purification, 903.0 mg of colorless liquid was obtained with a yield of 85.1%. 1 H NMR (400 MHz, CDCl 3)δ7.79(d,J=8.1Hz,1H),7.34(d,J=8.1Hz,1H),5.08(d,J=8.7Hz,1H),4.28(s,1H),4.24(m,2H),4.17-4.13(m,2H),3.67( m,4H),3.57(m,4H),2.44(s,3H),1.97(m,1H),1.85(m,1H),1.43(s,9H),1.23-1.08(m,1H),0.92(m,3H),0.90(d,J=7.2Hz 3H).

[0091] 1.4.3. Preparation of N-tert-butyloxycarbonyl isoleucine ester bridged bromide (N-Boc-Ile-O-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.04 g (2.0 mmol) of N-tert-butyloxycarbonyl isoleucine ester bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 723.9 mg of colorless liquid was obtained by separation and purification, with a yield of 84.9%. 1 H NMR (400 MHz, CDCl 3 )δ5.12(d,J=6.4Hz,1H),3.99-3.88(m,1H),3.82(t,J=6.1Hz,2H),3.65(m,4H),3.56(m,2H),3.49(t,J=6.1Hz ,4H),2.14(m,1H),1.87(m,1H),1.44(s,9H),1.21-1.03(m,1H),0.93(d,J=7.9Hz,3H),0.91(t,J=8.1Hz,3H); 13 C NMR (101 MHz, CDCl 3 )δ171.58,155.84,79.80,71.15,70.40,70.21,69.81,59.22,39.15,37.49,30.34,28.33,24.82,15.56,11.58.

[0092] 1.4.4. Preparation of N-tert-butyloxycarbonyl isoleucine ester bridged borocalcin sodium (N-Boc-Ile-O-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valine ester bridged bromine was replaced with 106.6 mg (0.25 mmol) of N-tert-butyloxycarbonyl isoleucine ester bridged bromine, and prepared according to the experimental procedure 1.1.4. 85.4 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 63.0%.

[0093] 1.4.5. Preparation of isoleucine ester bridged borosulfate (Ile-O-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate was replaced with 75.9 mg (0.14 mmol) of N-tert-butyloxycarbonyl isoleucine ester bridged borosulfate, and prepared according to the experimental procedure 1.1.5. 50.1 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 80.9%. 1 H NMR (400 MHz, D 2 O)δ:3.95-3.88(m,2H),3.70(S,6H),3.65-3.59(m,2H),3.57-3.51(m,1H),3.39-3.23(m,2H),2.76-2.69(m,1H),1.93-0.82(m,14H); 13 C NMR (400MHz, D 2 O)δ:173.68,81.30,79.95,70.76,68.50,68.05,60.84,50.72,34.19,23.35,16.16,11.88. All data confirmed that the compound was L-isoleucine (2-(2-(2-(sodium dodecaborylmercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (Leu-O-BSH), and its structure is as follows:

[0094]

[0095] 1.5. Preparation of Methionine Ester-bridged Boron Card (Met-O-BSH)

[0096] Synthesized in 5 steps.

[0097] 1.5.1. The experimental steps are the same as 1.1.1.

[0098] 1.5.2. Preparation of N-tert-butyloxycarbonylmethionine ester bridged p-toluenesulfonate (N-Boc-Met-O-TrG Ts): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.75 g (3.0 mmol) of N-Boc-L-methionine and prepared according to the experimental procedure 1.1.2. After separation and purification, 1.32 g of colorless liquid was obtained with a yield of 82.3%. 1 H NMR (400 MHz, CDCl 3)δ7.80(d,J=7.8Hz,2H),7.35(d,J=7.8Hz,2H),5.19(s,1H),4.43(s,1H),4.37-4.22(m,2H),4.20-4.14(m,2H),3.69 (dd,J=9.9,4.8Hz,4H),3.59(s,4H),2.54(t,J=7.5Hz,2H),2.45(s,3H),2.09(s,3H),2.03-1.74(m,2H),1.45(s,9H).

[0099] 1.5.3. Preparation of N-tert-butyloxycarbonylmethionine ester bridged bromide (N-Boc-Met-O-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonylvaline ester bridged p-toluenesulfonate was replaced with 1.07 g (2.0 mmol) of N-tert-butyloxycarbonylmethionine ester bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 719.9 mg of colorless liquid was obtained by separation and purification, with a yield of 81.0%. 1 H NMR (400 MHz, CDCl 3 )δ5.18(d,J=7.0Hz,1H),4.41(s,1H),4.35-4.19(m,2H),3.80(dd,J=12.2,6.1Hz,2H),3.70(t,J=4.5Hz,2H),3.68-3.5 7(m,4H),3.46(t,J=6.2Hz,2H),2.53(t,J=7.5Hz,2H),2.18-2.09(m,2H),2.08(s,3H),2.00-1.85(m,1H),1.42(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ172.17,154.93,79.94,71.18,70.59,68.85,64.31,52.73,30.59,29.83,28.26,15.37.

[0100] 1.5.4. Preparation of N-tert-butyloxycarbonylmethionine ester bridged borocarbamide sodium (N-Boc-Met-O-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromide was replaced with 111.1 mg (0.25 mmol) of N-tert-butyloxycarbonylmethionine ester bridged bromide, prepared according to experimental procedure 1.1.4. 91.6 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 65.4%.

[0101] 1.5.5. Preparation of methionine ester bridged borosulfate (Met-O-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate was replaced with 78.4 mg (0.14 mmol) of N-tert-butyloxycarbonyl methionine ester bridged borosulfate, and prepared according to the experimental procedure 1.1.5. 37.1 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 57.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ5.18(d,J=7.0Hz,1H),4.41(s,1H),4.35-4.19(m,2H),3.80(dd,J=12.2,6.1Hz,2H),3.70(t,J=4.5Hz,2H),3. 68-3.57(m,4H),3.46(t,J=6.2Hz,2H),2.53(t,J=7.5Hz,2H),2.18-2.09(m,2H),2.08(s,3H),2.00-1.85(m,1H); 13 C NMR (151 MHz, DMSO-d 6 )δ171.13,159.19,158.98,158.77,158.57,118.61,116.63,72.71,72.68,72.62,70.13,69.99,60.54,51.55,30.02,29.02,14.72. All data confirmed that the compound was L-methionine (2-(2-(2-(sodium dodecaboryl mercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (Met-O-BSH), and its structure is as follows:

[0102]

[0103] 1.6. Preparation of D-methionine ester-bridged borocard (Met-O-BSH)

[0104] Synthesized in 5 steps.

[0105] 1.6.1. The experimental steps are the same as 1.1.1.

[0106] 1.6.2. Preparation of N-tert-butyloxycarbonyl D-methionine ester bridged p-toluenesulfonate (N-Boc-D-Met-O-TrG Ts): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.75 g (3.0 mmol) of N-Boc-D-methionine and prepared according to the experimental procedure 1.1.2. After separation and purification, 1.32 g of colorless liquid was obtained with a yield of 82.3%. 1 H NMR (400 MHz, CDCl 3)δ7.81(d,J=7.8Hz,2H),7.34(d,J=7.9Hz,2H),5.18(s,1H),4.42(s,1H),4.36-4.21(m,2H),4.19-4.13(m,2H),3.68 (dd,J=9.8,4.7Hz,4H),3.58(s,4H),2.55(t,J=7.6Hz,2H),2.46(s,3H),2.11(s,3H),2.04-1.75(m,2H),1.45(s,9H).

[0107] 1.6.3. Preparation of N-tert-butyloxycarbonyl D-methionine ester bridged bromide (N-Boc-D-Met-O-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.07 g (2.0 mmol) of N-tert-butyloxycarbonyl D-methionine ester bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 719.7 mg of colorless liquid was obtained by separation and purification, with a yield of 80.9%. 1 H NMR (400 MHz, CDCl 3 )δ5.19(d,J=7.0Hz,1H),4.42(s,1H),4.34-4.18(m,2H),3.81(dd,J=12.3,6.2Hz,2H),3.71(t,J=4.5Hz,2H),3.67-3.5 6(m,4H),3.47(t,J=6.3Hz,2H),2.54(t,J=7.4Hz,2H),2.19-2.10(m,2H),2.09(s,3H),2.01-1.86(m,1H),1.43(s,9H); 13 CNMR (101MHz, CDCl 3 )δ172.18,154.94,79.93,71.17,70.58,68.86,64.32,52.72,30.58,29.84,28.27,15.36.

[0108] 1.6.4. Preparation of N-tert-butyloxycarbonyl D-methionine ester bridged borosulfate (N-Boc-D-Met-O-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valine ester bridged bromide was replaced with 111.1 mg (0.25 mmol) of N-tert-butyloxycarbonyl D-methionine ester bridged bromide, prepared according to the experimental procedure 1.1.4. 91.8 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 65.5%.

[0109] 1.6.5. Preparation of methionine ester bridged borosulfate (D-Met-O-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate was replaced with 78.4 mg (0.14 mmol) of N-tert-butyloxycarbonyl D-methionine ester bridged borosulfate, prepared according to the experimental procedure 1.1.5. 36.8 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 57.5%. 1 H NMR (400 MHz, DMSO-d 6 )δ5.17(d,J=7.1Hz,1H),4.42(s,1H),4.34-4.18(m,2H),3.81(dd,J=12.3,6.2Hz,2H),3.71(t,J=4.6Hz,2H),3. 67-3.56(m,4H),3.47(t,J=6.1Hz,2H),2.54(t,J=7.6Hz,2H),2.17-2.08(m,2H),2.09(s,3H),2.01-1.86(m,1H); 13 CNMR (151MHz, DMSO-d 6 )δ171.12,159.18,158.97,158.78,158.56,118.62,116.64,72.72,72.67,72.63,70.14,69.98,60.53,51.54,30.03,29.01,14.73. All data confirmed that the compound was D-methionine (2-(2-(2-(sodium dodecaboryl mercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (D-Met-O-BSH), and its structure is as follows:

[0110]

[0111] 1.7. Preparation of phenylalanine ester-bridged borocard (Phe-O-BSH)

[0112] Synthesized in 5 steps.

[0113] 1.7.1. The experimental steps are the same as 1.1.1.

[0114] 1.7.2. Preparation of N-tert-butyloxycarbonylphenylalanine ester bridged p-toluenesulfonate (N-Boc-Phe-O-TrG Ts): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.80 g (3.0 mmol) of N-Boc-phenylalanine and prepared according to the experimental procedure 1.1.2. After separation and purification, 1.35 g of colorless liquid was obtained with a yield of 81.6%. 1 H NMR (400 MHz, CDCl 3)δ7.78(d,J=8.2Hz,2H),7.33(d,J=8.2Hz,2H),7.30-7.19(m,3H),7.15(d,J=6.9Hz,2H),5.05(d,J=8.2Hz,1H),4.59(m, 1H),4.24(m,2H),4.17-4.11(m,2H),3.69-3.65(m,2H),3.63(m,2H),3.56(m,4H),3.08(m,2H),2.43(s,3H),1.41(s,9H).

[0115] 1.7.3. Preparation of N-tert-butyloxycarbonylphenylalanine ester bridged bromide (N-Boc-Phe-O-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonylvaline ester bridged p-toluenesulfonate was replaced with 1.10 g (2.0 mmol) of N-tert-butyloxycarbonylphenylalanine ester bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 778.7 mg of colorless liquid was obtained by separation and purification, with a yield of 84.8%. 1 H NMR (400 MHz, CDCl 3 )δ5.19(d,J=7.0Hz,1H),4.42(s,1H),4.34-4.18(m,2H),3.81(dd,J=12.3,6.2Hz,2H),3.71(t,J=4.5Hz,2H),3.67-3.5 6(m,4H),3.47(t,J=6.3Hz,2H),2.54(t,J=7.4Hz,2H),2.19-2.10(m,2H),2.09(s,3H),2.01-1.86(m,1H),1.43(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ172.18,154.94,79.93,71.17,70.58,68.86,64.32,52.72,30.58,29.84,28.27,15.36.

[0116] 1.7.4. Preparation of N-tert-butyloxycarbonylphenylalanine ester bridged borosulfate (N-Boc-Phe-O-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromide was replaced with 114.8 mg (0.25 mmol) of N-tert-butyloxycarbonylphenylalanine ester bridged bromide, prepared according to experimental procedure 1.1.4. 70.6 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 48.8%.

[0117] 1.7.5. Preparation of phenylalanine ester bridged borosulfate (Phe-O-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonylvaline ester bridged borosulfate was replaced with 81.0 mg (0.14 mmol) of N-tert-butyloxycarbonylphenylalanine ester bridged borosulfate, and prepared according to the experimental procedure 1.1.5. 53.6 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 80.1%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.54(s,1H),7.31-7.23(m,5H),4.31(s,1H),4.19(s,2H),3.86-3.46(m,10H),3.26-3.02(m,4H),2.00-0.65(m,10H); 13 C NMR (101 MHz, DMSO-d 6 )δ170.48,159.08,158.74,121.24,118.31,115.38,112.45,87.50,81.23,77.64,68.60,66.70,52.94,47.79,42.19,29.36. All data confirmed that the compound was phenylalanine (2-(2-(2-(sodium dodecaborylmercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (Phe-O-BSH), and its structure is as follows:

[0118]

[0119] 1.8. Preparation of D-phenylalanine ester-bridged boryl card (D-Phe-O-BSH)

[0120] Synthesized in 5 steps.

[0121] 1.8.1. The experimental steps are the same as 1.1.1.

[0122] 1.8.2. Preparation of N-tert-butyloxycarbonyl D-phenylalanine ester bridged p-toluenesulfonate (N-Boc-D-Phe-O-TrG Ts): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.80 g (3.0 mmol) of N-Boc-D-phenylalanine and prepared according to the experimental procedure 1.1.2. After separation and purification, 1.37 g of colorless liquid was obtained with a yield of 81.7%. 1 H NMR (400 MHz, CDCl 3)δ7.79(d,J=8.3Hz,2H),7.34(d,J=8.2Hz,2H),7.31-7.18(m,3H),7.16(d,J=6.8Hz,2H),5.06(d,J=8.3Hz,1H),4.58(m, 1H),4.25(m,2H),4.18-4.12(m,2H),3.68-3.64(m,2H),3.62(m,2H),3.57(m,4H),3.07(m,2H),2.42(s,3H),1.42(s,9H).

[0123] 1.8.3. Preparation of N-tert-butoxycarbonyl D-phenylalanine ester bridged bromide (N-Boc-D-Phe-O-TrG Br): 1.01 g (2.0 mmol) of N-tert-butoxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.10 g (2.0 mmol) of N-tert-butoxycarbonyl D-phenylalanine ester bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 778.5 mg of colorless liquid was obtained by separation and purification, with a yield of 84.7%. 1 H NMR (400 MHz, CDCl 3 )δ5.18(d,J=7.1Hz,1H),4.43(s,1H),4.35-4.19(m,2H),3.82(dd,J=12.4,6.3Hz,2H),3.72(t,J=4.5Hz,2H),3.68-3.5 7(m,4H),3.46(t,J=6.2Hz,2H),2.53(t,J=7.3Hz,2H),2.18-2.11(m,2H),2.08(s,3H),2.02-1.87(m,1H),1.42(s,9H); 13 CNMR (101MHz, CDCl 3 )δ172.19,154.95,79.92,71.16,70.57,68.85,64.33,52.71,30.57,29.85,28.26,15.37.

[0124] 1.8.4. Preparation of N-tert-butyloxycarbonyl D-phenylalanine ester bridged borosulfate (N-Boc-D-Phe-O-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valine ester bridged bromide was replaced with 114.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl D-phenylalanine ester bridged bromide, prepared according to the experimental procedure 1.1.4. 70.8 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 48.9%.

[0125] 1.8.5. Preparation of D-phenylalanine ester bridged borosulfate (D-Phe-O-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate was replaced with 81.0 mg (0.14 mmol) of N-tert-butyloxycarbonyl D-phenylalanine ester bridged borosulfate, and prepared according to the experimental procedure 1.1.5. 53.8 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 80.2%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.55(s,1H),7.32-7.24(m,5H),4.32(s,1H),4.18(s,2H),3.87-3.45(m,10H),3.27-3.03(m,4H),2.02-0.67(m,10H); 13 C NMR (101 MHz, DMSO-d 6 )δ170.47,159.06,158.75,121.23,118.32,115.39,112.46,87.51,81.24,77.65,68.62,66.71,52.93,47.78,42.17,29.54. All data confirmed that the compound was D-phenylalanine (2-(2-(2-(sodium dodecaborylmercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (D-Phe-O-BSH), and its structure is as follows:

[0126]

[0127] 1.9. Preparation of tryptophan ester-bridged borocard (Trp-O-BSH)

[0128] Synthesized in 5 steps.

[0129] 1.9.1. The experimental steps are the same as 1.1.1.

[0130] 1.9.2. Preparation of N-tert-butyloxycarbonyltryptophan ester bridged p-toluenesulfonate (N-Boc-Trp-O-TrG Ts): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.91 g (3.0 mmol) of N-Boc-tryptophan and prepared according to the experimental procedure 1.1.2. After separation and purification, 1.24 g of colorless liquid was obtained with a yield of 70.3%. 1 HNMR (400MHz, CDCl 3)δ8.68(s,1H),7.76(d,J=8.1Hz,2H),7.57(d,J=7.8Hz,1H),7.35(t,J=7.4Hz,1 H),7.29(d,J=9.5Hz,2H),7.16(t,J=7.4Hz,1H),7.10(d,J=7.7Hz,2H),5.19(d,J =8.0Hz,1H),4.67(d,J=7.4Hz,1H),4.17-4.12(m,2H),3.69-3.64(m,2H),3.64- 3.53(m,6H),3.53-3.47(m,2H),3.30(d,J=4.9Hz,2H),2.42(s,3H),1.45(s,9H).

[0131] 1.9.3. Preparation of N-tert-butyloxycarbonyltryptophan ester bridged bromide (N-Boc-Trp-O-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonylvaline ester bridged p-toluenesulfonate was replaced with 1.18 g (2.0 mmol) of N-tert-butyloxycarbonyltryptophan ester bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 796.0 mg of colorless liquid was obtained by separation and purification, with a yield of 79.9%. 1 H NMR (400 MHz, CDCl 3 )δ8.51(s,1H),7.59(d,J=7.9Hz,1H),7.36(d,J=8.0Hz,1H),7.19(t,J=7.5Hz,1H),7.13(d,J=7.7Hz,1H),7.08(s,1H),5.17(d,J=7.9Hz,1 H),4.69(d,J=7.1Hz,1H),4.25(m,2H),3.80(t,J=6.0Hz,2H),3.78-3.53(m,6H),3.46(t,J=6.1Hz,2H),3.32(d,J=5.0Hz,2H),1.45(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ172.26,155.48,136.25,127.88,123.35,121.99,119.51,118.74,111.3 4,109.70,79.91,71.18,70.49,70.45,68.90,64.56,54.62,30.61,28.38.

[0132] 1.9.4. Preparation of N-tert-butyloxycarbonyltryptophan ester bridged borosulfate (N-Boc-Trp-O-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromide was replaced with 124.5 mg (0.25 mmol) of N-tert-butyloxycarbonyltryptophan ester bridged bromide, prepared according to the experimental procedure 1.1.4. 75.3 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 48.8%.

[0133] 1.9.5. Preparation of tryptophan ester bridged borosulfate (Trp-O-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate was replaced with 86.4 mg (0.14 mmol) of N-tert-butyloxycarbonyl tryptophan ester bridged borosulfate, and prepared according to the experimental procedure 1.1.5. 58.4 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 80.6%. 1 H NMR (400 MHz, D 2 O)δ:7.68-7.58(dd,1H),7.52(d,1H,J=8),7.30-7.23(m,2H),7.18-7.14(m,1H),4.46-4.43(m,1H),4.36-4.31(m,1H),4.24-4.21(m,1H ),3.90-3.84(m,1H),3.77-3.73(m,2H),3.70-3.68(m,3H),3.62-3.58(m,2H),3.52-3.44(m,2H),3.42-3.28(m,2H),2.07-0.85(m,3H); 13 CNMR(400MHz,D 2 O)δ:170.86,141.92,131.87,125.34,119.58,114.53,114.09,107.04,99.76,94.81,84.38,70.99,67.00,65.87,52.62,44.79,26.95. All data confirmed that the compound was tryptophan (2-(2-(2-(sodium dodecaboryl mercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (Trp-O-BSH), and its structure is as follows:

[0134]

[0135] 1.10. Preparation of Tyr-O-BSH

[0136] Synthesized in 5 steps.

[0137] 1.10.1. The experimental steps are the same as 1.1.1.

[0138] 1.10.2. Preparation of N-tert-butyloxycarbonyltyrosine ester bridged p-toluenesulfonate (N-Boc-Tyr-O-TrG Ts): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.84 g (3.0 mmol) of N-Boc-tyrosine and prepared according to the experimental procedure 1.1.2. After separation and purification, 1.41 g of colorless liquid was obtained with a yield of 82.6%. 1 HNMR (400MHz, CDCl 3 )δ7.80(d,J=7.7Hz,2H),7.35(d,J=7.7Hz,2H),7.01(d,J=7.6Hz,2H),6.76(d,J=7.5Hz,2H),5.08(d,J=7.9H z, 1H), 4.55 (d, J = 6.3Hz, 1H), 4.29 (m, 2H), 4.19 (m, 2H), 3.63 (m, 8H), 3.03 (s, 2H), 2.45 (s, 3H), 1.44 (s, 9H).

[0139] 1.10.3. Preparation of N-tert-butyloxycarbonyltyrosine ester bridged bromide (N-Boc-Tyr-O-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonylvaline ester bridged p-toluenesulfonate was replaced with 1.13 g (2.0 mmol) of N-tert-butyloxycarbonyltyrosine ester bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 790.6 mg of colorless liquid was obtained by separation and purification, with a yield of 83.2%. 1 H NMR (400 MHz, CDCl 3 )δ7.01(d,J=7.7Hz,2H),6.75(d,J=7.6Hz,2H),5.06(d,J=7.7Hz,1H),4.73(m,2H),4.57(d,J=6.3Hz,1H) ,4.29(m,2H),3.82(t,J=6.1Hz,2H),3.77-3.62(m,4H),3.48(t,J=6.1Hz,2H),3.03(s,2H),1.44(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ172.07,155.23,155.04,130.60,130.22,115.68,80.08,74.78,71.41,70.60,68.95,64.29,54.65,37.64,30.35,28.23.

[0140] 1.10.4. Preparation of N-tert-butyloxycarbonyltyrosine ester bridged borosulfate (N-Boc-Tyr-O-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromide was replaced with 118.8 mg (0.25 mmol) of N-tert-butyloxycarbonyltyrosine ester bridged bromide, prepared according to the experimental procedure 1.1.4. 69.1 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 46.5%.

[0141] 1.10.5. Preparation of tyrosine ester bridged borosulfate (Tyr-O-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonylvaline ester bridged borosulfate was replaced with 83.2 mg (0.14 mmol) of N-tert-butyloxycarbonyltyrosine ester bridged borosulfate, and prepared according to the experimental procedure 1.1.5. 60.9 mg of colorless viscous liquid was obtained after separation and purification, with a yield of 88.0%. 1 H NMR(400MHz,DMSO-d6)δ7.01(d,J=7.7Hz,2H),6.75(d,J=7.6Hz,2H),3.97-3.68(m ,6H),3.49-3.43(m,4H),3.26-3.17(m,3H),2.83-2.32(m,4H),2.25-0.10(m,11H); 13 C NMR (400MHz, DMSO-d6) δ 172.87, 158.65, 132.50, 128.42, 118.72, 108.71, 105.40, 76.59, 72.74, 71.20, 68.76, 66.75, 54.19, 51.32, 43.42, 29.24. All data confirmed that the compound was tyrosine (2-(2-(2-(sodium dodecaborylmercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (Tyr-O-BSH), and its structure is as follows:

[0142]

[0143] 1.11. Preparation of dihydroxyphenylalanine ester-bridged boronic acid (Dpa-O-BSH)

[0144] Synthesized in 5 steps.

[0145] 1.11.1. The experimental steps are the same as 1.1.1.

[0146] 1.11.2. Preparation of N-tert-butyloxycarbonyl dihydroxyphenylalanine ester bridged p-toluenesulfonate (N-Boc-Dpa-O-TrG Ts): Replace 0.65 g (3.0 mmol) of N-Boc-L-valine with 0.89 g (3.0 mmol) of N-Boc-dihydroxyphenylalanine and prepare according to the experimental procedure 1.1.2. After separation and purification, 1.47 g of colorless liquid was obtained with a yield of 84.2%. 1 H NMR (400 MHz, CDCl 3 )δ7.79(d,J=7.6Hz,2H),7.36(d,J=7.5Hz,2H),6.87(d,J=7.5Hz,1H),6.76(s,1H),6.72(d,J=7.5Hz,1H),5.08(d, J=7.9Hz,1H),4.54(d,J=6.2Hz,1H),4.28(m,2H),4.17(m,2H),3.62(m,8H),3.04(s,2H),2.43(s,3H),1.45(s,9H).

[0147] 1.11.3. Preparation of N-tert-butyloxycarbonyl dihydroxyphenylalanine ester bridged bromide (N-Boc-Dpa-O-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.17 g (2.0 mmol) of N-tert-butyloxycarbonyl dihydroxyphenylalanine ester bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 835.9 mg of colorless liquid was obtained by separation and purification, with a yield of 85.1%. 1 H NMR (400 MHz, CDCl 3 )δ6.92(d,J=7.6Hz,1H),6.75(s,1H),6.73(d,J=7.6Hz,1H),5.07(d,J=7.5Hz,1H),4.74(m,2H),4.56(d,J=6.4 Hz,1H),4.28(m,2H),3.83(t,J=6.2Hz,2H),3.76-3.61(m,4H),3.47(t,J=6.1Hz,2H),3.02(s,2H),1.45(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ172.08,155.24,155.05,130.61,130.21,115.69,80.07,74.79,71.42,70.61,68.96,64.28,54.64,37.65,30.34,28.25.

[0148] 1.11.4. Preparation of N-tert-butyloxycarbonyl dihydroxyphenylalanine ester bridged borocarbamide sodium (N-Boc-Dpa-O-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valine ester bridged bromide was replaced with 118.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl dihydroxyphenylalanine ester bridged bromide, prepared according to the experimental procedure 1.1.4. 72.6 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 47.6%.

[0149] 1.11.5. Preparation of dihydroxyphenylalanine ester bridged borocarboxylate (Tyr-O-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borocarboxylate was replaced with 85.4 mg (0.14 mmol) of N-tert-butyloxycarbonyl dihydroxyphenylalanine ester bridged borocarboxylate, and prepared according to the experimental procedure 1.1.5. 63.4 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 88.7%. 1 HNMR(400MHz,DMSO-d6)δ6.92(d,J=7.6Hz,1H),6.75(s,1H),6.73(d,J=7.6Hz,1H),3.97- 3.68(m,6H),3.49-3.43(m,4H),3.26-3.17(m,3H),2.83-2.32(m,4H),2.25-0.10(m,11H); 13 C NMR (400MHz, DMSO-d6) δ 172.87, 158.65, 132.50, 128.42, 118.72, 108.71, 105.40, 76.59, 72.74, 71.20, 68.76, 66.75, 54.19, 51.32, 43.42, 29.32. All data confirmed that the compound was dihydroxyphenylalanine (2-(2-(2-(sodium dodecaborylmercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (Dpa-O-BSH), and its structure is as follows:

[0150]

[0151] 1.12. Preparation of His-O-BSH

[0152] Synthesized in 5 steps.

[0153] 1.12.1. The experimental steps are the same as 1.1.1.

[0154] 1.12.2. Preparation of N-tert-butyloxycarbonylhistidine ester bridged p-toluenesulfonate (N-Boc-His-O-TrG Ts): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.77 g (3.0 mmol) of N-Boc-histidine and prepared according to the experimental procedure 1.1.2. After separation and purification, 1.35 g of colorless liquid was obtained with a yield of 83.2%. 1 HNMR (400MHz, CDCl 3 )δ8.76(s,1H),7.76(d,J=7.5Hz,2H),7.65(s,1H),7.46(d,J=7.4Hz,2H),7.41(m,1H),6.73(d,J=7.5Hz,1H),5.06(d ,J=7.7Hz,1H),4.53(d,J=6.1Hz,1H),4.26(m,2H),4.15(m,2H),3.63(m,8H),3.05(s,2H),2.45(s,3H),1.46(s,9H).

[0155] 1.12.3. Preparation of N-tert-butyloxycarbonylhistidine ester bridged bromide (N-Boc-His-O-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonylvaline ester bridged p-toluenesulfonate was replaced with 1.08 g (2.0 mmol) of N-tert-butyloxycarbonylhistidine ester bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 757.2 mg of colorless liquid was obtained by separation and purification, with a yield of 84.3%. 1 H NMR (400 MHz, CDCl 3 )δ8.76(s,1H),7.65(s,1H),5.03(d,J=7.3Hz,1H),4.71(m,2H),4.57(d,J=6.2Hz,1H),4.25(m, 2H),3.85(t,J=6.1Hz,2H),3.77-3.62(m,4H),3.49(t,J=5.9Hz,2H),3.01(s,2H),1.46(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ171.53,155.27,136.34,124.82,118.12,80.05,74.76,71.43,70.61,68.95,64.26,54.65,37.64,30.35,28.26.

[0156] 1.12.4. Preparation of N-tert-butyloxycarbonylhistidine ester bridged borocarbamide sodium (N-Boc-His-O-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromide was replaced with 112.3 mg (0.25 mmol) of N-tert-butyloxycarbonylhistidine ester bridged bromide, prepared according to experimental procedure 1.1.4. 72.9 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 51.3%.

[0157] 1.12.5. Preparation of histidine ester bridged borosulfate (Tyr-O-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate was replaced with 79.6 mg (0.14 mmol) of N-tert-butyloxycarbonyl histidine ester bridged borosulfate, and prepared according to the experimental procedure 1.1.5. 58.5 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 89.2%. 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),7.68(s,1H),3.98-3.67(m,6H),3.51-3.45(m,4H),3.27-3.18(m,3H),2.84-2.33(m,4H),2.26-0.11(m,11H); 13 C NMR (400MHz, DMSO-d6) δ 172.83, 132.50, 136.42, 135.72, 118.12, 76.54, 72.73, 71.21, 68.75, 66.74, 54.18, 51.31, 43.41, 29.34. All data confirmed that the compound was histidine (2-(2-(2-(sodium dodecaborylmercapto)ethyl)oxyethyl)oxyethyl) alcohol ester (His-O-BSH), and its structure is as follows:

[0158]

[0159]

[0160] Example 2. Preparation of aminoamide bridged borocard (AA-N-BSH)

[0161] 2.1. Preparation of Valinamide-bridged Boron Card (Val-N-BSH)

[0162] Synthesized in 5 steps.

[0163] 2.1.1. Preparation of N-tert-butyloxycarbonyl valinamide bridged alcohol (N-Boc-Val-N-TrG OH): Weigh 0.65 g (3.0 mmol) of N-Boc-L-valine in a 50 ml round-bottom flask, add 20 ml of dry dichloromethane, put in a magnetic bar, and stir to dissolve the substrate. Place the reaction flask in an ice bath for 5 minutes, add EDCI (0.69 g, 3.6 mmol) and DMAP (0.11 g, 0.9 mmol) in turn, keep stirring in the ice bath for 10 minutes, then add 2-[2-(2-aminoethoxy)ethoxy]ethanol (0.54 g, 3.6 mmol), continue stirring in the ice bath for 5 minutes and then transfer to room temperature for reaction for 12 hours. TLC detection shows complete conversion (developing solvent: PE / EA=1 / 1). The reaction solution is washed with purified water (3×20 ml), 1 mol / L HCl (3×20 ml), saturated NaHCO 3 The organic phases were combined, dried, and concentrated to obtain the residue, which was purified by silica gel column chromatography (200-300 mesh, eluent: PE / EA=1 / 1 to 0 / 1) to obtain 845.1 mg of the target product with a yield of 80.9%. 1 H NMR(400MHz,DMSO)δ7.87(s,1H),6.57(s,1H),4.59(s,1H),3.81-3.70(m,1H) ,3.50(m,2H),3.35(m,10H),1.88(m,1H),1.38(s,9H),0.82(d,J=6.8Hz,6H).

[0164] 2.1.2. Preparation of N-tert-butoxycarbonyl valinamide bridged p-toluenesulfonate (N-Boc-Val-N-TrG Ts): Weigh 0.70 g (2.0 mmol) of N-tert-butoxycarbonyl valinamide bridged alcohol and dissolve it in 20 ml of dry dichloromethane. Stir it in an ice bath for 5 minutes, then slowly add 0.55 ml (4.0 mmol) of triethylamine, and then add 417.9 mg (2.0 mmol) of TsCl. Keep the reaction in an ice bath for 30 minutes, then warm it to room temperature for 12 hours. TLC detection shows that the reaction is completely converted (developing solvent: PE / EA = 1 / 1), wash it with purified water (20 ml × 3), 1M HCl ((3 × 20 ml)), dry it, filter it, concentrate it, and purify it by silica gel column chromatography (200-300 mesh, eluent: PE / EA = 1 / 1) to obtain 927.1 mg of colorless oil, with a yield of 92.3%. 1 H NMR (400 MHz, CDCl 3)δ7.79(d,J=8.2Hz,2H),7.33(d,J=8.1Hz,2H),6.54(s,1H),5.21(d,J=7.8Hz,1H),4.19-4.12(m,2H),3.90(s,1H),3.72-3.64(m,2H),3. 60-3.52(m,4H),3.51(t,J=5.4Hz,2H),3.43(m,2H),2.43(s,3H),2.09(m,1H),1.41(s,9H),0.92(d,J=6.7Hz,3H),0.88(d,J=6.8Hz,3H).

[0165] 2.1.3. Preparation of N-tert-butoxycarbonyl valinamide bridged bromide (N-Boc-Val-N-TrG Br): 1.01 g (2.0 mmol) of N-tert-butoxycarbonyl valinamide bridged p-toluenesulfonate was replaced with 1.00 g (2.0 mmol) of N-tert-butoxycarbonyl valinamide bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 755.5 mg of colorless liquid was obtained by separation and purification, with a yield of 92.1%. 1 H NMR (400 MHz, CDCl 3 )δ7.86(m,1H),6.51(m,1H),4.91(s,1H),4.11(s,1H),3.84(t,J=6.1Hz,2H),3.67(m,4H), 3.58(t,J=4.9Hz,2H),3.54–3.48(m,4H),1.69(m,1H),1.46(s,9H),0.96(d,J=5.5Hz,5H); 13 C NMR (101 MHz, CDCl 3 )δ172.62,155.46,79.97,71.18,70.43,70.25,69.83,67.49,41.71,39.18,30.29,28.33,24.77.

[0166] 2.1.4. Preparation of N-tert-butyloxycarbonyl valinamide bridged borosulfate (N-Boc-Val-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valinamide bridged bromide was replaced with 102.5 mg (0.25 mmol) of N-tert-butyloxycarbonyl valinamide bridged bromide, and prepared according to the experimental procedure 1.1.4. 78.9 mg of colorless oil was obtained after separation and purification, with a yield of 59.6%.

[0167] 2.1.5. Preparation of Val-N-BSH: 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valinamide bridged borosulfate was replaced with 74.1 mg (0.14 mmol) of N-tert-butyloxycarbonyl valinamide bridged borosulfate according to the experimental procedure 1.1.5. 54.8 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 91.2%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.41(s,2H),7.95(s,1H),3.76(s,2H),3.54(s,4H),3.51(s,1H),3.16(s,2 H),2.89(s,2H),2.73(s,2H),1.90(s,1H),1.23(br,11H),0.92–0.85(m,6H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.57,158.80,158.60,158.39,158.19,120.72,118.73,116.74,114.75,70.10,69.86,69.23,66.53,51.50,24.12,22.94,21.59. All data confirmed that the compound was N-(2-(2-(2-sodium dodecaborylmercapto)ethoxy)ethoxy)ethyl L-valinamide (Val-N-BSH), and its structure is as follows:

[0168]

[0169] 2.2. Preparation of Leucylamide-bridged Boron Card (Leu-N-BSH)

[0170] Synthesized in 5 steps.

[0171] 2.2.1. Preparation of N-tert-butyloxycarbonylleucinamide bridged alcohol (N-Boc-Leu-N-TrG OH): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.69 g (3.0 mmol) of N-Boc-L-leucine and prepared according to the experimental procedure 2.1.1. After separation, purification and concentration, 1.02 g of the target product was obtained with a yield of 93.8%. 1 H NMR (400 MHz, CDCl 3)δ7.09(s,1H),5.28(s,1H),4.11(s,1H),3.73(m,2H),3.65-3.57(m,6H),3.54(t,J=4.8Hz,2H), 3.44(d,J=5.1Hz,1H),3.36(m,2H),1.61(m,2H),1.46(m,1H),1.40(s,9H),0.90(d,J=2.7Hz,6H).

[0172] 2.2.2. Preparation of N-tert-butoxycarbonyl leucinamide bridged p-toluenesulfonate (N-Boc-Leu-N-TrG Ts): 0.70 g (2.0 mmol) of N-tert-butoxycarbonyl valinamide bridged alcohol was replaced with 0.72 g (2.0 mmol) of N-tert-butoxycarbonyl leucinamide bridged alcohol and prepared according to the experimental procedure 2.1.2. 931.3 mg of colorless oil was obtained after separation and purification, with a yield of 90.2%. 1 HNMR (400MHz, CDCl 3 )δ7.78(d,J=7.8Hz,2H),7.33(d,J=7.8Hz,2H),6.66(s,1H),5.08(s,1H),4.16(m,2H),4.10(d,J=7.0Hz,1H),3.68(m,2 H), 3.52 (m, 6H), 3.41 (t, J = 4.9Hz, 2H), 2.43 (s, 3H), 1.61 (m, 2H), 1.51-1.44 (m, 1H), 1.41 (s, 9H), 0.90 (d, J = 5.6Hz, 6H).

[0173] 2.2.3. Preparation of N-tert-butoxycarbonylleucinamide bridged bromide (N-Boc-Leu-N-TrG Br): 1.01 g (2.0 mmol) of N-tert-butoxycarbonylvaline ester bridged p-toluenesulfonate was replaced with 1.03 g (2.0 mmol) of N-tert-butoxycarbonylleucinamide bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 692.2 mg of colorless liquid was obtained by separation and purification, with a yield of 81.6%. 1 H NMR (400 MHz, CDCl 3 )δ6.54(s,1H),4.95(s,1H),4.12(s,1H),3.83(t,J=6.1Hz,2H),3.67(m,4H),3.58(t,J =4.9Hz,2H),3.51(m,4H),1.68(m,2H),1.48(m,1H),1.45(s,9H),0.95(d,J=5.6Hz,6H); 13 C NMR (101 MHz, CDCl 3)δ172.66,155.59,79.87,71.16,70.41,70.23,69.82,53.09,41.69,39.22,30.35,28.32,24.75,22.96.

[0174] 2.2.4. Preparation of N-tert-butyloxycarbonylleucinamide bridged borosulfate (N-Boc-Leu-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromide was replaced with 106.0 mg (0.25 mmol) of N-tert-butyloxycarbonylleucinamide bridged bromide, prepared according to the experimental procedure 1.1.4. 71.2 mg of colorless oil was obtained after separation and purification, with a yield of 60.2%.

[0175] 2.2.5. Preparation of Leucylamide-bridged Boron Sodium (Leu-N-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonylvaline ester-bridged Boron Sodium was replaced with 76.1 mg (0.14 mmol) of N-tert-butyloxycarbonylleucylamide-bridged Boron Sodium, and prepared according to the experimental procedure 1.1.5. 46.6 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 77.5%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.75-8.66(m,1H),8.30(s,2H),3.77-3.75(m,1H),3.55-3.47(m,5H),3.45-3.39(m,3H),3.35-3.28(m,1H),3.25-3.11( m,2H),1.97-1.89(m,1H),1.68-1.58(m,1H),1.57-1.50(m,2H),1.49-0.92(m,7H),0.86(t,J=24Hz,6H),0.79-0.10(m,3H); 13 CNMR (400MHz, DMSO-d 6 )δ167.59,82.86,72.37,70.66,67.52,60.77,49.60,41.47,40.68,26.27,22.59,21.32. All data confirmed that the compound was N-(2-(2-(2-sodium dodecaborylmercapto)ethoxy)ethoxy)ethyl L-leucinamide (Leu-N-BSH), and its structure is as follows:

[0176]

[0177] 2.3. Preparation of D-leucinamide-bridged borocard (D-Leu-N-BSH)

[0178] Synthesized in 5 steps.

[0179] 2.3.1. Preparation of N-tert-butyloxycarbonyl D-leucinamide bridged alcohol (N-Boc-D-Leu-N-TrG OH): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.69 g (3.0 mmol) of N-Boc-L-leucine and prepared according to the experimental procedure 2.1.1. After separation, purification and concentration, 1.03 g of the target product was obtained with a yield of 93.9%. 1 HNMR (400MHz, CDCl 3 )δ7.08(s,1H),5.27(s,1H),4.12(s,1H),3.72(m,2H),3.66-3.56(m,6H),3.53(t,J=4.8Hz,2H), 3.43(d,J=5.1Hz,1H),3.35(m,2H),1.62(m,2H),1.47(m,1H),1.41(s,9H),0.91(d,J=2.7Hz,6H).

[0180] 2.3.2. Preparation of N-tert-butyloxycarbonyl D-leucinamide bridged p-toluenesulfonate (N-Boc-D-Leu-N-TrG Ts): 0.70 g (2.0 mmol) of N-tert-butyloxycarbonyl valinamide bridged alcohol was replaced with 0.72 g (2.0 mmol) of N-tert-butyloxycarbonyl D-leucinamide bridged alcohol and prepared according to the experimental procedure 2.1.2. 932.4 mg of colorless oil was obtained after separation and purification, with a yield of 90.3%. 1 H NMR (400 MHz, CDCl 3 )δ7.79(d,J=7.8Hz,2H),7.34(d,J=7.8Hz,2H),6.67(s,1H),5.09(s,1H),4.15(m,2H),4.11(d,J=7.0Hz,1H),3.67(m,2 H), 3.53 (m, 6H), 3.42 (t, J = 4.9Hz, 2H), 2.42 (s, 3H), 1.63 (m, 2H), 1.52-1.45 (m, 1H), 1.42 (s, 9H), 0.89 (d, J = 5.6Hz, 6H).

[0181] 2.3.3. Preparation of N-tert-butyloxycarbonyl D-leucinamide bridged bromide (N-Boc-D-Leu-N-TrG Br):

[0182] 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate was replaced by 1.03 g (2.0 mmol) of N-tert-butyloxycarbonyl D-leucylamide bridged p-toluenesulfonate, prepared according to the experimental procedure 1.1.3. 664.5 mg of colorless liquid was obtained by separation and purification, with a yield of 78.3%. 1 H NMR (400 MHz, CDCl 3 )δ6.56(s,1H),4.97(s,1H),4.13(s,1H),3.84(t,J=6.1Hz,2H),3.68(m,4H),3.56(t,J =4.9Hz,2H),3.53(m,4H),1.67(m,2H),1.49(m,1H),1.43(s,9H),0.97(d,J=5.6Hz,6H); 13 C NMR (101 MHz, CDCl 3 )δ172.68,155.61,79.86,71.15,70.43,70.25,69.83,53.07,41.68,39.23,30.36,28.33,24.74,22.95.

[0183] 2.3.4. Preparation of N-tert-butyloxycarbonylleucinamide bridged borosulfate (N-Boc-D-Leu-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromide was replaced with 106.0 mg (0.25 mmol) of N-tert-butyloxycarbonyl D-leucinamide bridged bromide, prepared according to the experimental procedure 1.1.4. 74.0 mg of colorless oil was obtained after separation and purification, with a yield of 62.6%.

[0184] 2.3.5. Preparation of leucineamide bridged borosulfate (D-Leu-N-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate was replaced with 76.1 mg (0.14 mmol) of N-tert-butyloxycarbonyl D-leucineamide bridged borosulfate according to the experimental procedure 1.1.5. 49.4 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 82.2%. 1 H NMR (400 MHz, DMSO-d 6)δ8.74-8.65(m,1H),8.28(s,2H),3.78-3.76(m,1H),3.56-3.48(m,5H),3.43-3.36(m,3H),3.36-3.29(m,1H),3.23-3.08( m,2H),1.96-1.87(m,1H),1.66-1.56(m,1H),1.56-1.51(m,2H),1.47-0.93(m,7H),0.87(t,J=24Hz,6H),0.78-0.12(m,3H); 13 CNMR (400MHz, DMSO-d 6 )δ167.61,82.87,72.38,70.67,67.53,60.78,49.62,41.46,40.67,26.25,22.57,21.34. All data confirmed that the compound was N-(2-(2-(2-sodium dodecaborylmercapto)ethoxy)ethoxy)ethyl D-leucinamide (D-Leu-N-BSH), and its structure is as follows:

[0185]

[0186] 2.4. Preparation of Isoleucylamide-bridged Boron Card (Ile-N-BSH)

[0187] Synthesized in 5 steps.

[0188] 2.4.1. Preparation of N-tert-butyloxycarbonyl isoleucinamide bridged alcohol (N-Boc-Ile-N-TrG OH): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.69 g (3.0 mmol) of N-Boc-L-isoleucine and prepared according to the experimental procedure 2.1.1. After separation, purification and concentration, 892.2 mg of the target product was obtained with a yield of 82.1%. 1 HNMR(400MHz,DMSO)δ7.87(s,1H),6.61(d,J=9.0Hz,1H),4.59(t,J=5.4Hz,1H ),3.78(t,J=8.2Hz,1H),3.50(m,4H),3.41(m,4H),3.36(m,4H),1.64(m,1H),

[0189] 1.42(m,1H),1.37(s,9H),1.15–0.99(m,1H),0.81(d,J=7.4Hz,3H),0.79(d,J=6.7Hz,3H).

[0190] 2.4.2. Preparation of N-tert-butoxycarbonyl isoleucinamide bridged p-toluenesulfonate (N-Boc-Ile-N-TrG Ts): 0.70 g (2.0 mmol) of N-tert-butoxycarbonyl valinamide bridged alcohol was replaced with 0.72 g (2.0 mmol) of N-tert-butoxycarbonyl isoleucinamide bridged alcohol and prepared according to the experimental procedure 2.1.2. 935.4 mg of colorless oil was obtained after separation and purification, with a yield of 90.6%. 1 H NMR (400 MHz, CDCl 3 )δ7.80(d,J=8.2Hz,2H),7.34(d,J=8.2Hz,2H),6.54(s,1H),5.17(d,J= 7.9Hz,1H),4.21-4.15(m,2H),3.99-3.88(m,1H),3.72-3.65(m,2H),3.6 2-3.49(m,6H),3.44(m,2H),2.44(s,3H),1.83(m,1H),1.47(m,1H),1.42 (s,9H),1.19-1.03(m,1H),0.91(d,J=4.0Hz,3H),0.89(d,J=4.5Hz,3H).

[0191] 2.4.3. Preparation of N-tert-butoxycarbonyl isoleucinamide bridged bromide (N-Boc-Ile-N-TrG Br): 1.01 g (2.0 mmol) of N-tert-butoxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.03 g (2.0 mmol) of N-tert-butoxycarbonyl isoleucinamide bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 736.3 mg of colorless liquid was obtained by separation and purification, with a yield of 86.8%. 1 H NMR (400 MHz, CDCl 3 )δ6.98-6.13(s,1H),5.12(d,J=6.4Hz,1H),3.99-3.88(m,1H),3.82(t,J=6.1Hz,2H),3.65(m,4H),3.56(m,2H),3.49(t ,J=6.0Hz,4H),2.14(m,1H),1.87(m,1H),1.44(s,9H),1.21-1.03(m,1H),0.93(d,J=3.3Hz,3H),0.91(t,J=8.1Hz,3H); 13 C NMR (101 MHz, CDCl 3 )δ171.28,156.14,79.73,71.15,70.40,70.21,69.81,59.24,39.15,37.61,30.46,28.44,24.71,15.55,11.47.

[0192] 2.4.4. Preparation of N-tert-butyloxycarbonyl isoleucineamide bridged borosulfate (N-Boc-Ile-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valine ester bridged bromide was replaced with 106.0 mg (0.25 mmol) of N-tert-butyloxycarbonyl isoleucineamide bridged bromide, prepared according to the experimental procedure 1.1.4. 83.3 mg of colorless oil was obtained after separation and purification, with a yield of 61.3%.

[0193] 2.4.5. Preparation of Ile-N-BSH: 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester-bridged boryl sodium was replaced with 76.1 mg (0.14 mmol) of N-tert-butyloxycarbonyl isoleucyl amide-bridged boryl sodium, and prepared according to the experimental procedure 1.1.5. 47.0 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 75.8%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.52(s,1H),8.18(s,2H),4.91-4.43(m,8H),3.74(s,2H),3.63-3.38(m,6H),3.26-3.04(m,2H),1.77-0.94(m,11H),0.90-0.58(s,6H); 13 C NMR (101 MHz, DMSO-d 6 )δ168.26,118.53,115.58,70.21,70.14,69.90,69.24,56.92,42.03,36.50,24.62,14.86,11.61. All data confirmed that the compound was N-(2-(2-(2-sodium dodecaborylmercapto)ethoxy)ethoxy)ethyl L-isoleucinamide (Ile-N-BSH), and its structure is as follows:

[0194]

[0195] 2.5. Preparation of Methionamide-bridged Boron Card (Met-N-BSH)

[0196] Synthesized in 5 steps.

[0197] 2.5.1. Preparation of N-tert-butyloxycarbonylmethionamide bridged alcohol (N-Boc-Met-N-TrG OH): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.75 g (3.0 mmol) of N-Boc-L-methionine and prepared according to the experimental procedure 2.1.1. After separation, purification and concentration, 947.8 mg of the target product was obtained with a yield of 83.1%.1 H NMR (400 MHz, CDCl 3 )δ7.11(s,1H),5.54(d,J=7.3Hz,1H),4.24(s,1H),3.72(m,2H),3.68–3.56(m,6H),3.53(t,J=4.6Hz, 2H),3.46–3.34(m,2H),3.23(s,1H),2.48(m,2H),2.06(s,3H),2.01(m,1H),1.85(m,1H),1.40(s,9H).

[0198] 2.5.2. Preparation of N-tert-butyloxycarbonylmethionamide bridged p-toluenesulfonate (N-Boc-Met-N-TrG Ts): 0.70 g (2.0 mmol) of N-tert-butyloxycarbonylvalinamide bridged alcohol was replaced with 0.76 g (2.0 mmol) of N-tert-butyloxycarbonylmethionamide bridged alcohol, and prepared according to the experimental procedure 2.1.2. 1.01 g of colorless oil was obtained after separation and purification, with a yield of 94.1%. 1 H NMR (400 MHz, CDCl 3 )δ7.76(d,J=7.7Hz,2H),7.31(d,J=7.8Hz,2H),6.73(s,1H),5.40(d,J=8.0Hz,1H),4.22(s,1H),4.13(m,2H),3.6 6(m,2H),3.52(m,6H),3.40(m,2H),2.50(m,2H),2.41(s,3H),2.05(m,1H),2.04(s,3H),1.87(m,1H),1.39(s,9H).

[0199] 2.5.3. Preparation of N-tert-butyloxycarbonylmethionamide bridged bromide (N-Boc-Met-N-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonylvaline ester bridged p-toluenesulfonate was replaced with 1.07 g (2.0 mmol) of N-tert-butyloxycarbonylmethionamide bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 733.9 mg of colorless liquid was obtained by separation and purification, with a yield of 83.0%. 1 H NMR (400 MHz, CDCl 3)δ6.64(s,1H),5.27(s,1H),4.27(s,1H),3.82(t,J=6.1Hz,2H),3.65(m,4H),3.57(t,J=4.9Hz,2H),3.5 4-3.43(m,4H),2.59-2.53(m,2H),2.11(s,3H),2.07(m,1H),1.91(td,J=14.3,7.2Hz,1H),1.44(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ171.28,155.47,80.03,71.14,70.49,70.22,69.67,53.44,39.28,30.45,30.14,28.38,15.35,15.28.

[0200] 2.5.4. Preparation of N-tert-butyloxycarbonylmethionamide bridged borosulfate (N-Boc-Met-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromide was replaced with 110.5 mg (0.25 mmol) of N-tert-butyloxycarbonylmethionamide bridged bromide, prepared according to experimental procedure 1.1.4. 103.6 mg of colorless oil was obtained after separation and purification, with a yield of 73.8%.

[0201] 2.5.5. Preparation of Methionamide-bridged Boron Sodium (Met-N-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester-bridged Boron Sodium was replaced with 78.6 mg (0.14 mmol) of N-tert-butyloxycarbonyl methionamide-bridged Boron Sodium according to the experimental procedure 1.1.5. 50.3 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 77.9%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.61(s,1H),8.27(s,2H),3.87-3.68(m,2H),3.58-3.49(m,3H),3.47-3.43(m, 3H),3.25-3.07(m,2H),2.52-2.44(m,2H),2.06-1.95(m,3H),1.68-0.46(m,13H); 13 CNMR (101MHz, DMSO-d 6)δ168.55,70.17,69.85,69.19,52.05,42.05,39.23,31.38,28.61,15.02. All data confirmed that the compound was N-(2-(2-(2-sodium dodecaboryl mercapto)ethoxy)ethoxy)ethyl L-methionamide (Met-N-BSH), and its structure is as follows:

[0202]

[0203] 2.6. Preparation of D-Methionamide-bridged Boron Card (D-Met-N-BSH)

[0204] Synthesized in 5 steps.

[0205] 2.6.1. Preparation of N-tert-butyloxycarbonyl D-methionamide bridged alcohol (N-Boc-D-Met-N-TrG OH): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.75 g (3.0 mmol) of N-Boc-D-methionine and prepared according to the experimental procedure 2.1.1. After separation, purification and concentration, 948.2 mg of the target product was obtained with a yield of 83.2%. 1 H NMR (400 MHz, CDCl 3 )δ7.12(s,1H),5.53(d,J=7.3Hz,1H),4.23(s,1H),3.74(m,2H),3.69-3.57(m,6H),3.54(t,J=4.6Hz, 2H),3.47-3.35(m,2H),3.24(s,1H),2.47(m,2H),2.08(s,3H),2.03(m,1H),1.86(m,1H),1.41(s,9H).

[0206] 2.6.2. Preparation of N-tert-butyloxycarbonyl D-methionamide bridged p-toluenesulfonate (N-Boc-D-Met-N-TrG Ts): 0.70 g (2.0 mmol) of N-tert-butyloxycarbonyl valinamide bridged alcohol was replaced with 0.76 g (2.0 mmol) of N-tert-butyloxycarbonyl methionamide bridged alcohol, and prepared according to the experimental procedure 2.1.2. 1.03 g of colorless oil was obtained after separation and purification, with a yield of 94.3%. 1 H NMR (400 MHz, CDCl 3)δ7.75(d,J=7.7Hz,2H),7.32(d,J=7.8Hz,2H),6.72(s,1H),5.41(d,J=8.0Hz,1H),4.23(s,1H),4.12(m,2H),3.6 7(m,2H),3.53(m,6H),3.41(m,2H),2.51(m,2H),2.42(s,3H),2.06(m,1H),2.05(s,3H),1.86(m,1H),1.38(s,9H).

[0207] 2.6.3. Preparation of N-tert-butyloxycarbonyl D-methionamide bridged bromide (N-Boc-D-Met-N-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.07 g (2.0 mmol) of N-tert-butyloxycarbonyl methionamide bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 733.7 mg of colorless liquid was obtained by separation and purification, with a yield of 82.8%. 1 H NMR (400 MHz, CDCl 3 )δ6.65(s,1H),5.28(s,1H),4.26(s,1H),3.83(t,J=6.1Hz,2H),3.64(m,4H),3.56(t,J=4.9Hz,2H),3.5 5-3.42(m,4H),2.58-2.54(m,2H),2.12(s,3H),2.08(m,1H),1.92(td,J=14.3,7.2Hz,1H),1.45(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ171.27,155.48,80.05,71.12,70.47,70.23,69.68,53.45,39.26,30.43,30.12,28.35,15.37,15.26.

[0208] 2.6.4. Preparation of N-tert-butyloxycarbonyl D-methionamide bridged borosulfate (N-Boc-D-Met-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valine ester bridged bromide was replaced with 110.5 mg (0.25 mmol) of N-tert-butyloxycarbonyl D-methionamide bridged bromide, prepared according to the experimental procedure 1.1.4. 103.4 mg of colorless oil was obtained after separation and purification, with a yield of 73.7%.

[0209] 2.6.5. Preparation of D-Met-N-BSH: 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester-bridged borax sodium was replaced with 78.6 mg (0.14 mmol) of N-tert-butyloxycarbonyl methionamide-bridged borax sodium, and prepared according to the experimental procedure 1.1.5. 50.6 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 78.0%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.63(s,1H),8.25(s,2H),3.85-3.67(m,2H),3.57-3.48(m,3H),3.46-3.42(m, 3H),3.24-3.05(m,2H),2.51-2.43(m,2H),2.05-1.94(m,3H),1.67-0.45(m,13H); 13 C NMR (101 MHz, DMSO-d 6 )δ168.56,70.15,69.83,69.17,52.03,42.02,39.26,31.37,28.63,15.05. All data confirmed that the compound was N-(2-(2-(2-dodecaboryl sodium mercapto)ethoxy)ethoxy)ethyl D-methionamide (D-Met-N-BSH), and its structure is as follows:

[0210]

[0211]

[0212] 2.7. Preparation of Phenylalaninamide-bridged Boron Card (Phe-N-BSH)

[0213] Synthesized in 5 steps.

[0214] 2.7.1. Preparation of N-tert-butyloxycarbonylphenylalaninamide bridged alcohol (N-Boc-Phe-N-TrG OH): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.80 g (3.0 mmol) of N-Boc-L-phenylalanine and prepared according to the experimental procedure 2.1.1. After separation, purification and concentration, 1.17 g of the target product was obtained with a yield of 98.4%. 1 H NMR (400 MHz, CDCl 3 )δ7.16(m,5H),4.32(s,1H),3.66(m,2H),3.52(m,8H),3.31(m,4H),3.00(m,1H),2.89(m,1H),1.28(s,9H).

[0215] 2.7.2. Preparation of N-tert-butyloxycarbonylphenylalaninamide bridged p-toluenesulfonate (N-Boc-Phe-N-TrG Ts): 0.70 g (2.0 mmol) of N-tert-butyloxycarbonylvalinamide bridged alcohol was replaced with 0.79 g (2.0 mmol) of N-tert-butyloxycarbonylphenylalaninamide bridged alcohol, and prepared according to experimental procedure 2.1.2. 939.8 mg of colorless oil was obtained after separation and purification, with a yield of 85.4%. 1 H NMR (400 MHz, CDCl 3 )δ7.80(d,J=8.3Hz,2H),7.35(d,J=8.1Hz,2H),7.32-7.25(m,2H),7.22(dd,J=8.0,6.4Hz,3H),6.35(s,1H),5.18(s,1H),4.32(d,J=6 .7Hz,1H),4.21-4.13(m,2H),3.71-3.66(m,2H),3.57-3.53(m,2H),3.47(m,4H),3.37(m,2H),3.04(m,2H),2.46(s,3H),1.38(s,9H).

[0216] 2.7.3. Preparation of N-tert-butyloxycarbonylphenylalaninamide bridged bromide (N-Boc-Phe-N-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.10 g (2.0 mmol) of N-tert-butyloxycarbonylphenylalaninamide bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 795.3 mg of colorless liquid was obtained by separation and purification, with a yield of 86.8%. 1 H NMR (400 MHz, CDCl 3 )δ7.30-7.23(m,2H),7.19(t,J=7.8Hz,3H),6.38(s,1H),5.21(s,1H),4.32(s,1H),3.7 5(t,J=6.0Hz,2H),3.57(m,2H),3.63–3.17(m,8H),3.02(d,J=5.7Hz,2H),1.38(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ171.55,155.23,136.99,129.11,128.50,126.77,79.87,71.03,70.37,70.18,69.60,53.96,39.15,30.29,30.21,28.27.

[0217] 2.7.4. Preparation of N-tert-butyloxycarbonylphenylalaninamide bridged borosulfate (N-Boc-Phe-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromide was replaced with 114.5 mg (0.25 mmol) of N-tert-butyloxycarbonylphenylalaninamide bridged bromide, prepared according to experimental procedure 1.1.4. 125.7 mg of colorless oil was obtained after separation and purification, with a yield of 87.1%.

[0218] 2.7.5. Preparation of phenylalanineamide bridged borosulfate (Phe-N-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate was replaced with 80.8 mg (0.14 mmol) of N-tert-butyloxycarbonyl phenylalanineamide bridged borosulfate according to the experimental procedure 1.1.5. 48.5 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 72.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.56(s,1H),7.29-7.23(m,5H),4.00(s,1H),3.34-3.20(m,8H),3.18-3.08 (m,2H),2.95-3.06(m,2H),1.89(s,3H),1.5-1.20(m,2H),0.86-0.44(m,11H); 13 C NMR (400 MHz, DMSO-d 6 )δ165.44,135.10,131.27,129.94,127.44,126.05,123.17,81.71,72.49,72.44,56.43,46.58,41.98,41.42,35.75. All data confirmed that the compound was N-(2-(2-(2-sodium dodecaborylmercapto)ethoxy)ethoxy)ethyl L-phenylalaninamide (Phe-N-BSH), and its structure is as follows:

[0219]

[0220] 2.8. Preparation of D-phenylalanineamide bridged borocard (D-Phe-N-BSH)

[0221] Synthesized in 5 steps.

[0222] 2.8.1. Preparation of N-tert-butyloxycarbonyl D-phenylalaninamide bridged alcohol (N-Boc-D-Phe-N-TrG OH): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.80 g (3.0 mmol) of N-Boc-D-phenylalanine and prepared according to the experimental procedure 2.1.1. After separation, purification and concentration, 1.15 g of the target product was obtained with a yield of 98.1%. 1 H NMR (400 MHz, CDCl 3 )δ7.18(m,5H),4.33(s,1H),3.67(m,2H),3.54(m,8H),3.32(m,4H),3.03(m,1H),2.87(m,1H),1.29(s,9H).

[0223] 2.8.2. Preparation of N-tert-butoxycarbonyl D-phenylalaninamide bridged p-toluenesulfonate (N-Boc-D-Phe-N-TrG Ts): 0.70 g (2.0 mmol) of N-tert-butoxycarbonyl valinamide bridged alcohol was replaced with 0.79 g (2.0 mmol) of N-tert-butoxycarbonyl D-phenylalaninamide bridged alcohol and prepared according to experimental procedure 2.1.2. 939.5 mg of colorless oil was obtained after separation and purification, with a yield of 85.3%. 1 H NMR (400 MHz, CDCl 3 )δ7.78(d,J=8.3Hz,2H),7.36(d,J=8.1Hz,2H),7.33-7.26(m,2H),7.24(dd,J=8.0,6.4Hz,3H),6.36(s,1H),5.16(s,1H),4.34(d,J=6 .7Hz,1H),4.22-4.14(m,2H),3.72-3.67(m,2H),3.56-3.52(m,2H),3.46(m,4H),3.38(m,2H),3.05(m,2H),2.47(s,3H),1.39(s,9H).

[0224] 2.8.3. Preparation of N-tert-butyloxycarbonyl D-phenylalaninamide bridged bromide (N-Boc-D-Phe-N-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.10 g (2.0 mmol) of N-tert-butyloxycarbonyl D-phenylalaninamide bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 796.2 mg of colorless liquid was obtained by separation and purification, with a yield of 87.0%. 1 H NMR (400 MHz, CDCl 3)δ7.32-7.24(m,2H),7.18(t,J=7.8Hz,3H),6.39(s,1H),5.22(s,1H),4.33(s,1 H),3.76(t,J=6.0Hz,2H),3.58(m,2H),3.64-3.18(m,8H),3.05(d,J=5.7Hz,2H),

[0225] 1.38(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ171.56,155.25,136.97,129.13,128.52,126.75,79.86,71.05,70.36,70.17,69.61,53.94,39.16,30.28,30.23,28.29.

[0226] 2.8.4. Preparation of N-tert-butyloxycarbonyl D-phenylalaninamide bridged borosulfate (N-Boc-D-Phe-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valine ester bridged bromide was replaced with 114.5 mg (0.25 mmol) of N-tert-butyloxycarbonyl D-phenylalaninamide bridged bromide, prepared according to experimental procedure 1.1.4. 126.2 mg of colorless oil was obtained after separation and purification, with a yield of 87.5%.

[0227] 2.8.5. Preparation of D-phenylalaninamide bridged borosulfate (D-Phe-N-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate was replaced with 80.8 mg (0.14 mmol) of N-tert-butyloxycarbonyl D-phenylalaninamide bridged borosulfate according to the experimental procedure 1.1.5. 49.4 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 73.1%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.58(s,1H),7.27-7.24(m,5H),4.01(s,1H),3.35-3.21(m,8H),3.17-3.06 (m,2H),2.96-3.07(m,2H),1.87(s,3H),1.6-1.22(m,2H),0.87-0.45(m,11H); 13 C NMR (400 MHz, DMSO-d 6)δ165.46,135.12,131.28,129.95,127.43,126.06,123.15,81.73,72.46,72.45,56.44,46.57,41.96,41.43,35.76. All data confirmed that the compound was N-(2-(2-(2-sodium dodecaborylmercapto)ethoxy)ethoxy)ethyl D-phenylalaninamide (D-Phe-N-BSH), and its structure is as follows:

[0228]

[0229] 2.9. Preparation of tryptophanamide-bridged borocard (Trp-N-BSH)

[0230] Synthesized in 5 steps.

[0231] 2.9.1. Preparation of N-tert-butyloxycarbonyltryptophanamide bridged alcohol (N-Boc-Trp-N-TrG OH): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.91 g (3.0 mmol) of N-Boc-L-tryptophan and prepared according to the experimental procedure 2.1.1. After separation, purification and concentration, 1.19 g of the target product was obtained with a yield of 91.1%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.80(s,1H),7.92(t,J=5.3Hz,1H),7.60(d,J=7.8Hz,1H),7.35(d,J=8.0Hz,1H ),7.15(s,1H),7.07(t,J=7.3Hz,1H),6.99(t,J=7.3Hz,1H),6.71(d,J=8.3Hz,1H), 4.64(s,1H),4.14(d,J=4.2Hz,1H),3.52(m,6H),3.48-3.40(m,2H),3.37(m,2H),3. 21(m,2H),3.10(dd,J=14.5,5.0Hz,1H),2.94(dd,J=14.5,8.7Hz,1H),1.34(s,9H).

[0232] 2.9.2. Preparation of N-tert-butyloxycarbonyltryptophanamide bridged p-toluenesulfonate (N-Boc-Trp-N-TrG Ts): 0.70 g (2.0 mmol) of N-tert-butyloxycarbonylvalinamide bridged alcohol was replaced with 0.87 g (2.0 mmol) of N-tert-butyloxycarbonyltryptophanamide bridged alcohol and prepared according to the experimental procedure 2.1.2. 1.11 g of colorless oil was obtained after separation and purification, with a yield of 94.6%. 1 HNMR (400MHz, CDCl 3)δ8.55(s,1H),7.79(d,J=8.2Hz,2H),7.68(d,J=7.7Hz,1H),7.37(d,J=8.0Hz, 1H),7.33(d,J=8.1Hz,2H),7.18(t,J=7.4Hz,1H),7.12(d,J=7.5Hz,1H),7.09(s ,1H),6.11(s,1H),5.34(s,1H),4.41(s,1H),4.20-4.07(m,2H),3.76-3.57(m, 2H), 3.46 (t, J = 4.0Hz, 2H), 3.31 (m, 6H), 3.16 (m, 2H), 2.45 (s, 3H), 1.44 (s, 9H).

[0233] 2.9.3. Preparation of N-tert-butyloxycarbonyltryptophanamide bridged bromide (N-Boc-Trp-N-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonylvaline ester bridged p-toluenesulfonate was replaced with 1.18 g (2.0 mmol) of N-tert-butyloxycarbonyltryptophanamide bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 832.2 mg of colorless liquid was obtained by separation and purification, with a yield of 83.7%. 1 H NMR (400 MHz, CDCl 3 )δ8.60(s,1H),7.67(d,J=7.7Hz,1H),7.37(d,J=8.0Hz,1H),7.19(t,J=7.5Hz,1H),7.12(t,J=7.4Hz,1H),7.07(s,1H),6.25(s, 1H),5.31(s,1H),4.43(s,1H),3.74(t,J=6.0Hz,2H),3.52(m,2H),3.44(t,J=6.1Hz,2H),3.34(m,6H),3.19(m,2H),1.44(s,9H); 13 CNMR (101MHz, CDCl 3 )δ171.57,154.86,136.31,127.56,123.44,122.12,119.77,119.01,111.26,1 10.56,79.97,71.01,70.32,70.07,69.47,55.33,39.23,30.40,28.81,28.35.

[0234] 2.9.4. Preparation of N-tert-butyloxycarbonyltryptophanamide bridged borosulfate (N-Boc-Trp-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromine was replaced with 124.3 mg (0.25 mmol) of N-tert-butyloxycarbonyltryptophanamide bridged bromine, and prepared according to the experimental procedure 1.1.4. 88.8 mg of colorless oil was obtained after separation and purification, with a yield of 57.6%.

[0235] 2.9.5. Preparation of tryptophanamide bridged borosulfate (Trp-N-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borosulfate was replaced with 86.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl tryptophanamide bridged borosulfate according to the experimental procedure 1.1.5. 63.3 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 87.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ11.00(s,1H),8.56(s,1H),8.16(s,2H),7.61(s,1H),7.34(s,1H),7.19(s,1H),7.06-6.98(m,2H),4.01-3.91(m,1H ),,3.78-3.63(m,2H),3.54-3.47(m,2H),3.37-3.32(m,1H),3.30-3.23(m,2H),3.19-3.05(m,4H),1.75-0.59(m,16H); 13 C NMR (101 MHz, DMSO-d 6 )δ168.95,136.65,127.52,125.27,121.66,118.94,118.90,111.97,107.33,70.18,69.89,69.63,69.19,66.46,53.26,41.07,39.28,27.71. All data confirmed that the compound was N-(2-(2-(2-sodium dodecaboryl mercapto)ethoxy)ethoxy)ethyl L-tryptophanamide (Trp-N-BSH), and its structure is as follows:

[0236]

[0237] 2.10. Preparation of Tyr-N-BSH

[0238] Synthesized in 5 steps.

[0239] 2.10.1. Preparation of N-tert-butyloxycarbonyltyrosinamide bridged alcohol (N-Boc-Tyr-N-TrG OH): Replace 0.65 g (3.0 mmol) of N-Boc-L-valine with 0.84 g (3.0 mmol) of N-Boc-L-tyrosine and prepare according to the experimental procedure 2.1.1. After separation, purification and concentration, 1.14 g of the target product was obtained with a yield of 92.2%. 1 H NMR (400 MHz, CDCl 3 )δ9.03(s,1H),8.05(m,1H),7.12(d,J=7.9Hz,2H),6.89(d,J=7.9Hz,2H),6.81(m,1H),5.42(d,J=7.9Hz,1H) ,5.01(s,2H),4.33(s,1H),3.71(m,2H),3.62-3.43(m,8H),3.38(m,2H),2.97(d,J=23.6Hz,2H),1.39(s,9H).

[0240] 2.10.2. Preparation of N-tert-butyloxycarbonyl tyrosinamide bridged p-toluenesulfonate (N-Boc-Tyr-N-TrG Ts): 0.70 g (2.0 mmol) of N-tert-butyloxycarbonyl valinamide bridged alcohol was replaced with 0.82 g (2.0 mmol) of N-tert-butyloxycarbonyl tyrosinamide bridged alcohol and prepared according to experimental procedure 2.1.2. 1.03 g of colorless oil was obtained after separation and purification, with a yield of 90.6%. 1 HNMR (400MHz, CDCl 3 )δ7.80(d,J=7.9Hz,2H),7.35(d,J=7.8Hz,2H),7.03(d,J=7.8Hz,2H),6.73(d,J=7.9Hz,2H),6.33(s,1H),5.27(s,1H ), 4.27 (s, 1H), 4.17 (m, 2H), 3.68 (m, 2H), 3.55 (m, 2H), 3.42 (m, 6H), 2.96 (d, J = 14.7Hz, 2H), 2.45 (s, 3H), 1.42 (s, 9H).

[0241] 2.10.3. Preparation of N-tert-butyloxycarbonyl tyrosinamide bridged bromide (N-Boc-Tyr-N-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.13 g (2.0 mmol) of N-tert-butyloxycarbonyl tyrosinamide bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 800.3 mg of colorless liquid was obtained by separation and purification, with a yield of 84.4%. 1 H NMR (400 MHz, CDCl 3)δ7.02(d,J=7.7Hz,2H),6.75(d,J=7.6Hz,2H),6.54(s,1H),5.36(s,1H),4.29(s,1H),3.79(t,J =5.9Hz,2H),3.62(m,2H),3.55(m,2H),3.52–3.43(m,4H),3.38(m,2H),2.95(m,2H),1.42(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ171.83,155.51,130.64,130.15,127.72,115.77,80.25,71.08,70.29,70.07,69.56,56.10,39.36,38.04,30.32,28.32.

[0242] 2.10.4. Preparation of N-tert-butyloxycarbonyltyrosinamide bridged borosulfate (N-Boc-Tyr-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonylvaline ester bridged bromine was replaced with 118.5 mg (0.25 mmol) of N-tert-butyloxycarbonyltyrosinamide bridged bromine, and prepared according to the experimental procedure 1.1.4. 84.7 mg of colorless oil was obtained after separation and purification, with a yield of 57.1%.

[0243] 2.10.5. Preparation of Tyr-N-BSH: 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester-bridged borax sodium was replaced with 83.1 mg (0.14 mmol) of N-tert-butyloxycarbonyl tryptophanamide-bridged borax sodium, and prepared according to the experimental procedure 1.1.5. 53.0 mg of colorless viscous liquid was obtained after separation and purification, with a yield of 76.8%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.52(s,1H),8.52(s,1H),8.38-8.13(m,2H),7.0(d,J=8Hz,1H),6.68(d,J=8Hz,1H),4.29-4.06(m,4H),3.95-3.88(m,1H),3.74 -3.69(m,1H),3.61-3.57(m,1H),3.39-3.33(m,2H),3.32-3.23(m,2H),2.97-2.84(m,2H),1.47-1.32(m,2H),1.20-0.82(m,11H); 13 C NMR (101 MHz, DMSO-d 6)δ170.38,159.19,132.95,130.88,129.69,119.19,116.20,78.06,69.93,69.64,68.97,61.53,48.98,44.05,41.49. All data confirmed that the compound was N-(2-(2-(2-sodium dodecaborylmercapto)ethoxy)ethoxy)ethyl L-tyrosinamide (Tyr-N-BSH), and its structure is as follows:

[0244]

[0245] 2.11. Preparation of dopamide-bridged borochar (Dpa-N-BSH)

[0246] Synthesized in 5 steps.

[0247] 2.11.1. Preparation of N-tert-butyloxycarbonyl dopamide bridged alcohol (N-Boc-Dpa-N-TrG OH): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.89 g (3.0 mmol) of N-Boc-L-dopa and prepared according to the experimental procedure 2.1.1. After separation, purification and concentration, 1.18 g of the target product was obtained with a yield of 91.7%. 1 H NMR (400 MHz, CDCl 3 )δ9.36(s,2H),8.03(m,1H),7.27(m,1H),6.89(d,J=7.8Hz,1H),6.76(m,1H),6.63(d,J=7.7Hz,2H),5.43(d,J=7.8H z,1H),5.03(s,2H),4.32(s,1H),3.73(m,2H),3.63-3.44(m,8H),3.37(m,2H),2.96(d,J=23.6Hz,2H),1.41(s,9H).

[0248] 2.11.2. Preparation of N-tert-butyloxycarbonyl dopamide bridged p-toluenesulfonate (N-Boc-Dpa-N-TrG Ts): 0.70 g (2.0 mmol) of N-tert-butyloxycarbonyl valinamide bridged alcohol was replaced with 0.86 g (2.0 mmol) of N-tert-butyloxycarbonyl dopamide bridged alcohol and prepared according to the experimental procedure 2.1.2. 1.05 g of colorless oil was obtained after separation and purification, with a yield of 90.5%. 1 HNMR (400MHz, CDCl 3)δ9.36(s,2H),8.03(m,1H),7.83(d,J=7.9Hz,2H),7.46(d,J=7.8Hz,2H),6.92(d,J=7.6Hz,1H),6.81(s,1H),6.73(d,J=7.8Hz,1H ), 5.26 (s, 1H), 4.25 (s, 1H), 4.18 (m, 2H), 3.69 (m, 2H), 3.56 (m, 2H), 3.43 (m, 6H), 2.95 (d, J = 14.7Hz, 2H), 2.46 (s, 3H), 1.43 (s, 9H).

[0249] 2.11.3. Preparation of N-tert-butyloxycarbonyl dopamide bridged bromide (N-Boc-Dpa-N-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.16 g (2.0 mmol) of N-tert-butyloxycarbonyl dopamide bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 836.2 mg of colorless liquid was obtained by separation and purification, with a yield of 85.3%. 1 H NMR (400 MHz, CDCl 3 )δ9.34(s,2H),8.04(m,1H),7.38(m,1H),7.02(d,J=7.7Hz,1H),6.87(s,1H),6.65(d,J=7.6Hz,2H),5.35(s,1H),4.2 7(s,1H),3.76(t,J=5.9Hz,2H),3.64(m,2H),3.56(m,2H),3.54-3.45(m,4H),3.39(m,2H),2.94(m,2H),1.44(s,9H); 13 C NMR (101 MHz, CDCl 3 )δ171.83,155.51,144.87,143.78,130.31,122.82,116.43,115.77,80.25,71.08,70.29,70.07,69.56,56.10,39.36,38.04,30.32,28.32.

[0250] 2.11.4. Preparation of N-tert-butyloxycarbonyl dopamide bridged borosulfate (N-Boc-Tyr-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valine ester bridged bromide was replaced with 122.5 mg (0.25 mmol) of N-tert-butyloxycarbonyl dopamide bridged bromide, prepared according to the experimental procedure 1.1.4. 90.5 mg of colorless oil was obtained after separation and purification, with a yield of 59.4%.

[0251] 2.11.5. Preparation of dopa-N-BSH: 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester-bridged borax sodium was replaced with 85.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl tryptophanamide-bridged borax sodium, and prepared according to the experimental procedure 1.1.5. 63.1 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 88.5%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.54(s,2H),8.52(m,1H),8.38-8.13(m,2H),6.93(d,J=8.1Hz,1H),6.87(s,1H),6.68(d,J=8.2Hz,1H),4.29-4.07(m,4H),3.96-3.89(m, 1H),3.75-3.68(m,1H),3.63-3.58(m,1H),3.37-3.32(m,2H),3.34-3 .25(m,2H),2.96-2.83(m,2H),1.48-1.33(m,2H),1.22-0.83(m,11H); 13 CNMR (101MHz, DMSO-d 6 )δ170.38,145.36,144.63,130.88,123.11,116.19,116.20,78.05,69.94,69.62,68.95,61.54,48.96,44.07,41.46. All data confirmed that the compound was N-(2-(2-(2-dodecaborylsodium mercapto)ethoxy)ethoxy)ethyl L-dopamide (Dpa-N-BSH), and its structure is as follows:

[0252]

[0253] 2.12. Preparation of Histidine-bridged Boron Card (His-N-BSH)

[0254] Synthesized in 5 steps.

[0255] 2.12.1. Preparation of N-tert-butyloxycarbonyl histidine amide bridged alcohol (N-Boc-His-N-TrG OH): 0.65 g (3.0 mmol) of N-Boc-L-valine was replaced with 0.77 g (3.0 mmol) of N-Boc-L-histidine and prepared according to the experimental procedure 2.1.1. After separation, purification and concentration, 1.11 g of the target product was obtained with a yield of 95.8%. 1 H NMR (400 MHz, CDCl 3)δ12.32(m,1H),8.67(m,1H),8.03(m,1H),7.68(m,1H),7.41(m,1H),4.85(m,1H ),3.68(m,2H),3.53(m,8H),3.32(m,4H),3.02(m,1H),2.87(m,1H),1.38(s,9H).

[0256] 2.12.2. Preparation of N-tert-butyloxycarbonyl histidine amide bridged p-toluenesulfonate (N-Boc-His-N-TrG Ts): 0.70 g (2.0 mmol) of N-tert-butyloxycarbonyl valinamide bridged alcohol was replaced with 0.77 g (2.0 mmol) of N-tert-butyloxycarbonyl histidine amide bridged alcohol and prepared according to the experimental procedure 2.1.2. 935.7 mg of colorless oil was obtained after separation and purification, with a yield of 86.6%. 1 H NMR (400 MHz, CDCl 3 )δ12.35(m,1H),8.69(m,1H),8.05(m,1H),7.82(d,J=8.2Hz,2H),7.66(m,1H),7.41(m,1H),7.37(d,J=8.1Hz,2H),5.19(m,1H),4.31(d, J=6.6Hz,1H),4.22-4.15(m,2H),3.73-3.65(m,2H),3.56-3.52(m,2H),3.48(m,4H),3.36(m,2H),3.05(m,2H),2.48(s,3H),1.39(s,9H).

[0257] 2.12.3. Preparation of N-tert-butyloxycarbonyl histidine amide bridged bromide (N-Boc-His-N-TrG Br): 1.01 g (2.0 mmol) of N-tert-butyloxycarbonyl valine ester bridged p-toluenesulfonate was replaced with 1.08 g (2.0 mmol) of N-tert-butyloxycarbonyl histidine amide bridged p-toluenesulfonate, and prepared according to the experimental procedure 1.1.3. 781.5 mg of colorless liquid was obtained by separation and purification, with a yield of 87.2%. 1 H NMR (400 MHz, CDCl 3 )δ12.38(m,1H),8.72(m,1H),8.02(m,1H),7.68(m,1H),7.42(m,1H),5.17(m,1H),4.34(s,1H ),3.78(t,J=6.0Hz,2H),3.56(m,2H),3.65-3.18(m,8H),3.04(d,J=5.7Hz,2H),1.39(s,9H); 13 C NMR (101 MHz, CDCl3 )δ171.58,155.36,136.42,131.35,118.02,79.84,71.02,70.35,70.16,69.62,53.95,39.12,30.26,30.22,28.28.

[0258] 2.12.4. Preparation of N-tert-butyloxycarbonyl histidine amide bridged borosulfate (N-Boc-His-N-TrG BSH): 102.8 mg (0.25 mmol) of N-tert-butyloxycarbonyl valine ester bridged bromide was replaced with 112.0 mg (0.25 mmol) of N-tert-butyloxycarbonyl histidine amide bridged bromide, prepared according to the experimental procedure 1.1.4. 126.5 mg of colorless oil was obtained after separation and purification, with a yield of 89.2%.

[0259] 2.12.5. Preparation of histidine amide bridged borocarboxylate sodium (His-N-BSH): 74.3 mg (0.14 mmol) of N-tert-butyloxycarbonyl valine ester bridged borocarboxylate sodium was replaced with 80.8 mg (0.14 mmol) of N-tert-butyloxycarbonyl histidine amide bridged borocarboxylate sodium, and prepared according to the experimental procedure 1.1.5. 58.0 mg of colorless viscous liquid was obtained by separation and purification, with a yield of 88.7%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.56(s,1H),12.12(m,1H),8.86(br,2H),8.63(m,1H),8.03(m,1H),7.62(m,1H),4.03(m,1H),3.36- 3.22(m,8H),3.17-3.06(m,2H),2.96-3.07(m,2H),1.87(s,3H),1.45-1.23(m,2H),0.87-0.45(m,11H); 13 C NMR (400 MHz, DMSO-d 6 )δ165.44,136.17,131.27,118.02,81.72,72.46,72.45,56.41,46.56,41.95,41.43,35.76. All data confirmed that the compound was N-(2-(2-(2-sodium dodecaborylmercapto)ethoxy)ethoxy)ethyl L-histidinamide (His-N-BSH), and its structure is as follows:

[0260]

[0261] Example 3 Cytotoxicity of Amino Acid-BSH Targeting Compounds

[0262] The cell culture medium containing peptide bovine serum was incubated at 37°C for 24 hours. The normal human liver cell LO2 cells were cultured in tissue culture medium to make 1×10 5 Prepare a cell suspension of 100 μl / mL, inoculate the cell suspension into a 96-well cell culture plate (100 μl / well), and culture it in a 37°C carbon dioxide incubator for 24 hours. After the cells adhere to the wall and grow, remove the supernatant, add the tissue culture medium of the control group (without drug) and the test group (with drug) for incubation, where the concentration of the drug in the cell culture medium is 500 μmol / L, and continue to culture in a 37°C carbon dioxide incubator. Take it out after 2 days of incubation. Add MTT solution and continue to culture for 4 hours. Remove the cell incubation solution, then add DMSO, shake for 10 minutes, and finally use an enzyme marker to measure the absorbance value at a wavelength of 570nm, and calculate the relative proliferation rate (RGR) of the cells according to the formula based on its absorbance. The calculation formula for the relative proliferation rate of cells is:

[0263]

[0264] The results are shown in Table 1. It can be seen that after the series of amino acid-BSH targeting compounds were incubated with normal human liver cells LO2 for 2 days, their RGRs were close to 100%, indicating that these compounds had no toxicity or very low toxicity to normal human liver cells at a concentration of 500 μmol / L.

[0265] Table 1. Relative cell proliferation rate (RGR) measured by MTT colorimetry

[0266]

[0267]

[0268] Example 4 Cellular Boron Uptake Characteristics of a Series of Amino Acid-BSH Targeting Compounds

[0269] The ICP-MS method was used to determine the boron uptake characteristics of a series of amino acid-BSH targeting compounds in human umbilical vein endothelial cells (HUVEC), human liver cancer cells HepG2, human breast cancer cells MDA-MB-231, and human glioma cells U87.

[0270] Specific process: Take tumor cells in the logarithmic growth phase and add appropriate amount of RPMI 1640 culture medium (10% fetal bovine serum, 100 U / ml penicillin) to adjust the cell concentration to 1×10 5 / ml, inoculated in 6-well culture plates, each well inoculated with 100μl of tumor cell suspension. After 24h of culture, the prepared test drug was added (the control group did not add drug) to a final drug concentration of 100μM, and placed in 5% CO 2After culturing at 37°C for 24 h in an incubator, the culture medium in the dish was removed with a pipette, washed with PBS (3 × 1 mL), 0.5 mL of trypsin was added to the dish, and then placed in a 37°C constant temperature CO 2 Culture in the incubator for 3 minutes, and observe whether the cells shrink and become round under a microscope during this period. After shrinking and becoming round, quickly add 0.6 ml of culture medium to terminate digestion, and gently blow the attached cells to make all the cells fall off from the bottom of the culture dish, then transfer the cell suspension to a centrifuge tube, dilute and count the number of cells in each well with a hemocytometer. Centrifuge the above cell suspension, remove the supernatant, and add PBS for washing (3×1 mL). Add 500 μL of concentrated nitric acid to the washed cell-containing centrifuge tube for digestion; use ICP-MS to measure the boron content in the cells and calculate the T / N ratio. The T / N ratio is defined as: the amount of boron uptake in tumor cells / the amount of boron loaded in HUVEC cells.

[0271] The results are shown in Tables 2 to 4. It can be seen that in the three tumor cell lines investigated, the boron loading of all amino acid-BSH targeting compounds was much greater than 10 9 B / cell, and their T / N ratios were all greater than 3.0, which met the prerequisites for being a boron delivery agent. All ester-type compounds showed better boron uptake characteristics than the corresponding amide-type compounds; in specific tumor cells, specific amino acid-BSH-targeted compounds showed better boron uptake characteristics than the positive control borocalcin sodium (BSH). For example, in HepG2 cells, the boron uptake characteristics of Met-O-BSH, D-Met-O-BSH, Tyr-O-BSH, Dpa-O-BSH, His-O-BSH, Trp-N-BSH and His-N-BSH were better than those of the positive control drug, especially Met-O-BSH, whose T / N value was 4 times that of BSH; in human breast cancer cells MDA-MB-231, the boron uptake characteristics of Leu-O-BSH, D-Leu-O-BSH, Met-O-BSH, D-Met-O-BSH, Tyr-O-BSH and Dpa-O-BSH were better than that of BSH; in human glioma cells U87, the boron uptake characteristics of Tyr-O-BSH and Dpa-O-BSH were better than those of BSH, especially Tyr-O-BSH, whose T / N value was 5.1 times that of BSH.

[0272] Table 2 Boron uptake characteristics of a series of amino acid-BSH targeting compounds in human liver cancer HepG2 cells

[0273]

[0274]

[0275] aThe T / N ratio is defined as: boron uptake by human hepatoma cell HepG2 / boron uptake by human umbilical vein endothelial cells HUVEC

[0276] Table 3 Boron uptake characteristics of a series of amino acid-BSH targeting compounds in human breast cancer cells MDA-MB-231

[0277]

[0278] a The T / N ratio is defined as: boron uptake of human breast cancer cells MDA-MB-231 / boron uptake of human umbilical vein endothelial cells HUVEC

[0279] Table 4 Boron uptake characteristics of a series of amino acid-BSH targeting compounds in human glioma U87 cells

[0280]

[0281]

[0282] a The T / N ratio is defined as: boron uptake of human glioma cells U87 / boron uptake of human umbilical vein endothelial cells HUVEC

[0283] Example 5 Hydrophilic and lipophilic characteristics of a series of amino acid-BSH targeting compounds

[0284] Experimental methods: a) Establish a detection standard curve for each sample to be tested. A series of amino acid-BSH targeting compounds were dissolved in enzymatic buffer (50mM Tris-HCl, 1.0M NaCl, pH 7.4), and 5 concentration gradients were set to 0.012725, 0.006363, 0.003181, 0.001591, and 0.000795μg / ml, respectively. The standard curve was drawn with the peak area as the ordinate and the drug concentration as the abscissa. This experiment was repeated 3 times; b) Prepare n-octanol saturated with aqueous solution and an aqueous solution saturated with n-octanol, mix n-octanol and water in equal proportions, stir for 24h to make the two phases mutually saturated, stand for stratification, separate the two phases, and store them separately for later use; c) Accurately weigh 10mg of the sample to be tested, put it in a 10mL volumetric flask, add n-octanol saturated with aqueous solution to dissolve the sample and dilute to the scale, accurately draw 8mL from it into a 25mL volumetric flask, and add 8mL of aqueous solution saturated with n-octanol. After shaking the 25mL volumetric flask for 3 hours, let it stand to separate the water phase and the oil phase, filter it through a 0.22μm filter membrane, inject 10μl each time, use HPLC to determine the peak area, and substitute it into the standard curve equation to calculate the content of the sample to be tested in each phase. The oil-water distribution coefficient calculation formula is:

[0285]

[0286] Experimental results: The results are shown in Table 5. It can be seen that the LogP value of the positive control drug BSH is -2.36±0.03, which is less than 1, indicating that BSH has high solubility in water, low passive diffusion permeability, poor absorption and brain permeability, and high renal clearance. Except for His-O-BSH and His-N-BSH, the LogP values ​​of the compounds described in the present invention are all greater than 0, indicating that such compounds have better permeability than BSH, increase binding with metabolic enzymes, and have a high degree of metabolism.

[0287] Table 5. Hydrophilicity coefficient (LogP) of a series of amino acid-BSH targeting compounds

[0288]

[0289] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. An amino acid-BSH targeting hybrid compound, the structure of which is shown in Formula I, in, X is any one of CHMe2, CH2CHMe2, CH(CH3)CH2CH3, CH2CH2SMe, Bn, CH2(3-Indoyl), CH2[4-(OH)Ph], CH2[3,4-bis(OH)Ph], CH2(4-Imidazolyl); the configuration of the carbon marked by * is R- or S-; Y can be O or NH; B is 10 B or natural boron; SNaB 12 H 11 The structure is as follows:

2. The amino acid-BSH targeting hybrid compound according to claim 1, characterized in that A specific compound selected from the group consisting of:

3. A method for preparing the amino acid-BSH targeting hybrid compound according to claim 1 or 2, characterized in that: When Y=0, the following steps are included: (1) Preparation of 2-(2-(2-hydroxyethoxy)ethoxy)ethyl active ester (TrG Es): Weigh triethylene glycol and dissolve it in dry redistilled dichloromethane (DCM), add a stirrer, add an appropriate amount of organic base under ice bath, add acylating agent in batches, stir and react at room temperature for about 30 minutes, keep the room temperature and continue to react for 12 hours, add an appropriate amount of DCM, wash with water, wash with acid, dry, and concentrate under reduced pressure. The synthetic route is as follows: (2) Preparation of N-tert-butyloxycarbonyl amino acid ester bridged active ester (N-Boc-AA-O-TrG Es): Weigh N-Boc amino acid and dissolve it in an appropriate amount of DCM. Place the reaction bottle in an ice bath for 5 minutes, add the condensing agent and 4-dimethylaminopyridine (DMAP) in turn, keep stirring in the ice bath for 10 minutes, then add TrG Es. After the addition is completed, continue to react in the ice bath for 30 minutes, then keep the reaction at room temperature for 12 hours. After the reaction is completed, add an appropriate amount of DCM, wash the DCM layer with water and 1N HCl in turn, dry, and concentrate to obtain the residue. Purify it by silica gel column chromatography and concentrate to obtain the target product. The synthetic route is as follows: (3) Preparation of N-tert-butyloxycarbonyl amino acid ester bridged bromine (N-Boc-AA-O-TrG-Br): Weigh the compound N-Boc-AA-O-TrG Es and dissolve it in an appropriate amount of acetone, add lithium bromide, place the reactor in an oil bath at an appropriate temperature and heat to react for 2 to 10 hours. After the reaction is completed, evaporate the solvent, add an appropriate amount of DCM, wash with water, dry, and separate and purify by column chromatography. The synthesis steps are as follows: (4) Preparation of N-tert-butyloxycarbonyl amino acid ester bridged borocalcin (N-Boc-AA-O-TrG-BSH): Weigh the compound N-Boc-AA-O-TrG Br and borocalcin sodium (Na2SB 12 H 11 ) is dissolved in an appropriate amount of dry acetonitrile, an inorganic base and potassium iodide are added under stirring, the reaction system is placed in an oil bath and heated under reflux for 5 to 10 hours, after the reaction is completed, the solvent is removed by rotary evaporation, and the residue is separated and purified by rapid column chromatography. The synthetic route is as follows: (5) Preparation of amino acid ester bridged borocard (AA-O-BSH): Weigh the compound N-Boc-AA-O-TrG-BSH and dissolve it in dry DCM. Cool it in an ice bath for 5 minutes, add acid while stirring, then warm it to room temperature and continue the reaction for 1 to 5 hours. TLC detection shows that the reaction is completely converted. The developing solvent is DCM / MeOH=1 / 1. Saturated sodium bicarbonate is used to adjust the pH of the reaction system to weak alkalinity. The solvent is removed by rotary evaporation. The residue is separated by column chromatography and freeze-dried to obtain the product. The synthetic route is as follows:

4. A method for preparing the amino acid-BSH targeting hybrid compound according to claim 1 or 2, characterized in that: When Y=NH, the process comprises the following steps: (1) Preparation of N-tert-butyloxycarbonylamino acid amide bridged alcohol (N-Boc-AA-N-TrG-OH): Weigh N-Boc amino acid and dissolve it in an appropriate amount of DCM. Place the reaction bottle in an ice bath for 5 minutes, add a condensing agent and an organic base in sequence, keep stirring in the ice bath for 10 minutes, then add 2-(2-(2-aminoethoxy)ethoxy)ethanol. After the addition is completed, continue to react in an ice bath for 30 minutes, then keep the reaction at room temperature for 12 hours. After the reaction is completed, add an appropriate amount of DCM. The DCM layer is washed with water and 1N HCl in sequence, dried, and concentrated to obtain a residue. Purify by silica gel column chromatography and concentrate to obtain the target product. The synthetic route is as follows: (2) Preparation of N-tert-butyloxycarbonyl amino acid amide bridged active ester (N-Boc-AA-N-TrG Es): Replace triethylene glycol with N-tert-butyloxycarbonyl amino acid amide bridged alcohol and prepare according to the method described in step (1) of claim 3. The synthetic route is as follows: (3) Preparation of N-tert-butoxycarbonyl amino acid amide bridged bromide (N-Boc-AA-N-TrG-Br): Replace the N-tert-butoxycarbonyl amino acid ester bridged active ester with N-tert-butoxycarbonyl amino acid amide bridged active ester, and prepare according to the method described in step (3) of claim 3. The synthetic route is as follows: (4) Preparation of N-tert-butyloxycarbonyl amino acid amide bridged borocarbyl (N-Boc-AA-N-TrG-BSH): Replace the N-tert-butyloxycarbonyl amino acid ester bridged bromine with N-tert-butyloxycarbonyl amino acid amide bridged bromine, and prepare according to the method described in step (4) of claim 3. The synthetic route is as follows: (5) Preparation of amino acid amide bridged boron card (AA-N-BSH): replace the N-tert-butyloxycarbonyl amino acid ester bridged boron card with the N-tert-butyloxycarbonyl amino acid amide bridged boron card, and prepare it according to the method described in step (5) of claim 3. The synthetic route is as follows:

5. The preparation method according to claim 3, characterized in that: In step (1), the molar ratio of triethylene glycol to the organic base is 1:1.1-1.5; the molar ratio of triethylene glycol to the acylating agent is 1:1.1-1.5; the organic base is any one of triethylamine, trimethylamine, and diisopropylethylamine; the acylating agent is any one of p-toluenesulfonyl chloride, methanesulfonyl chloride, and trifluoromethanesulfonyl chloride; In step (2), the molar ratios of N-Boc amino acid to condensing agent, DMAP and TrG Es are 1:1.1-1.5, 1:0.1-0.5 and 1:1.1-1.5 respectively; the condensing agent is any one of 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), ethyl chloroformate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), N,N'-diisopropylcarbodiimide (DIC) and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (PyBOP); In step (3), the molar ratio of N-Boc-AA-O-TrG Es to lithium bromide is 1:1.1-1.5; the reaction temperature is 40-100°C; In step (4), the molar ratios of N-Boc-AA-O-TrG-Br to sodium borocarbamide, inorganic base, and potassium iodide are 1.1-1.5:1, 1:2.0-5.0, and 1:2.0-5.0, respectively; the inorganic base is lithium carbonate, cesium carbonate, and potassium carbonate; In step (5), the molar ratio of N-Boc-AA-O-TrG-BSH to the acid is 1.0:100-250; the acid is trifluoroacetic acid (TFA) or hydrochloric acid.

6. The preparation method according to claim 4, characterized in that: In step (1), the molar ratio of N-Boc amino acid to condensing agent, organic base and 2-(2-(2-aminoethoxy)ethoxy)ethanol is 1:1.1-1.5, 1:2.0-5.0 and 1:1.1-1.5; the condensing agent is the same as step (2) of claim 3; the organic base is any one of diisopropylethylamine (DIPEA), triethylamine and 2,2,6,6-tetramethylpiperidine.

7. Use of the amino acid-BSH targeting hybrid compound as claimed in claim 1 or 2 and their physiologically acceptable salts in the preparation of a boron delivery agent for tumor boron neutron capture therapy (BNCT).

8. The use according to claim 7, characterized in that: The tumor is a brain tumor, a head and neck tumor, a liver cancer, a breast cancer, a lung cancer, a colon cancer, a cervical cancer or a prostate cancer.

9. The use according to claim 7, characterized in that: The physiologically acceptable salts are tartrate, sulfate, and hydrochloride.

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