Synthesis process for synthesizing (S)-4-dihydroxy boryl phenylalanine by silicon-based protection method

Abstract

The invention discloses a synthesis process for synthesizing (S)-4-dihydroxy boryl phenylalanine by a silicon-based protection method. Compared with the traditional method for protecting amino and carboxyl by using boryl, the preparation method disclosed by the invention has the advantages that a silicon-based protection method is used, and cyclic 2-siloxazolidinone-5 can be preferably generated with amino and carboxyl, so that the reaction of an amino terminal and a carboxyl terminal with boron-10 acid ester is avoided. According to the method, the dosage of boron-10 acid ester can be reduced, so that the atom economy of the technical route is improved, and the production cost of the medicine is reduced. In addition, the solid polyboron-10 acid ester is easy to prepare and store, so that the production and operation cost of the L-BPA can be further reduced by using the synthesis process of the solid polyboron-10 acid ester as the raw material.

Description

Technical Field

[0001] This invention belongs to the field of boron-10 isotope drug synthesis technology, specifically relating to a silicon-based protection method for synthesizing (S)-4-dihydroxyboronylphenylalanine. Background Technology

[0002] In the field of cancer treatment, scientists are constantly exploring and developing innovative therapies that are more effective and less toxic to improve local tumor control rates, patient survival rates, and quality of life. Boron neutron capture therapy (BNCT) is an innovative radiotherapy method that has the potential to become an effective treatment for cancer. First, the patient is injected with a boron-containing drug. This drug has a strong affinity for cancer cells and quickly accumulates within tumor cells, with very little accumulation in normal tissue. Then, the patient's tumor site is irradiated with thermal neutrons. When the thermal neutrons are trapped by boron-10 (boron-10) in the tumor cells... 10 B) Fission occurs during capture, producing highly destructive alpha particles and recoil particles. 7 Li nucleus (such as Li nucleus) Figure 1 (As shown). These particles have low penetrating power and release energy over short distances (<10 μm). Since a single cell is about 10 μm in size, the boron neutron capture reaction occurs within a single cell, which can precisely kill tumor cells while protecting normal tissue from damage.

[0003] Two key factors in BNCT's killing of tumor cells are boron-10 isotopes and thermal neutrons. Boron-10 is the most important, as it is present in high concentrations and selectively enters tumor cells. Currently, the basic principles for selecting boron-containing drugs for BNCT are: (a) low toxicity and low absorption by normal tissues, with a concentration ratio (T / N) greater than 2.5 between tumor and normal tissues and between tumor tissue and blood (T / B); (b) a boron-10 concentration greater than 20 ppm in the tumor, meaning each tumor cell must contain at least 10⁹ boron-10 atoms or approximately 20 μg of boron-10 atoms per gram of tumor tissue; and (c) during neutron irradiation, boron in the blood and normal tissues should be relatively rapidly eliminated from the body, while its residence time in the tumor should be long enough to meet the irradiation treatment duration. Currently, only BSH and L-BPA (e.g., [missing information]) are approved by the FDA for clinical research in BNCT. Figure 2 As shown in the figure, L-BPA was approved for marketing in Japan in March 2020, making it the world's first approved clinical drug for BNCT.

[0004] L-BPA, short for (S)-4-dihydroxyboronylphenylalanine, is transported via the L-amino acid transport system, a neutral amino acid transport mechanism. Tumor cells typically have high metabolic activity and highly express LAT1 protein on their surface. Therefore, L-BPA can specifically enter and accumulate in tumor cells through the LAT1 pathway, thus achieving the therapeutic goal of BNCT (benign nucleolysis-associated tumor cell therapy). Because L-BPA can penetrate the cell membrane and enter tumor cells, the neutron capture reaction of 10B can directly destroy the cell nucleus. Therefore, many researchers have actively developed methods suitable for synthesizing L-BPA, especially methods for synthesizing L-BPA with high boron-10 enrichment.

[0005] One commonly used strategy is to introduce a dihydroxyboron group into the naturally available L-phenylalanine skeleton, thereby forming a carbon-boron bond at the para-position of the α-aminocarboxylic acid substituent to synthesize L-BPA (see...). Figure 3 -III). Bull. Chem. Soc., Jpn. 2000, 73, 231 reported a method for catalyzing (S)-4-iodophenylalanine using the transition metal palladium (as shown in Figure III). Figure 3 -I) The method involves coupling with pinacolborane. However, boron-10 enriched pinacolborane is difficult to obtain. Therefore, the method in this literature is not suitable for the synthesis of L-BPA.

[0006] Recently, patent WO 2017 / 028751 A1 reported the use of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine as a starting material, followed by deprotonation of the amino and carboxyl groups with sodium hydride, and then reaction with an excess of boron-10 alkoxy ester to obtain a boron-protected 4-iodophenylalanine intermediate (e.g. Figure 4 (As shown). The intermediate reacts with isopropyl magnesium chloride·lithium chloride and boron-10 ester to form a carbon-boron bond. Finally, hydrolysis protection is performed under acidic and high temperature to yield (S)-4-dihydroxyboronylphenylalanine, i.e., L-BPA. Patent JP 2023-33957A also reports a synthetic route for (S)-4-dihydroxyboronylphenylalanine using trialkylboron protection. In the above methods, the boron-based raw material (boron-10 alkoxy ester or trialkylboron-10) plays a dual role as a protecting group and a borizing agent. Since the protection and borization processes cannot distinguish between boron-10 and boron-11 isotopes, an excess of boron-10 raw material is required to ensure sufficient protection and borization, resulting in high production costs. Summary of the Invention

[0007] The purpose of this invention is to overcome the above-mentioned problems and provide a silicon-based protected synthesis process for (S)-4-dihydroxyboronylphenylalanine. To achieve the above objective, this invention adopts the following technical solution:

[0008] A synthetic process for synthesizing (S)-4-dihydroxyboronylphenylalanine by a silicon-based protection method involves reacting (S)-N-tert-butoxycarbonyl-4-iodophenylalanine protected at the amino end with calcium hydride and dichlorosilane to obtain a class of siloxazolidinone intermediates.

[0009] The siloxazolidinone intermediate has a cyclic siloxazolidinone structure and can protect the amino and carboxyl groups of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine. The siloxazolidinone intermediate undergoes a deiodinated magnesium reaction at the aryl end using isopropyl magnesium chloride·lithium chloride, followed by a borylation reaction with a borizing agent to generate (S)-N-tert-butoxycarbonyl-4-pinacolborylphenylalanine.

[0010] (S)-4-dihydroxyboronylphenylalanine was prepared by deprotecting the tert-butoxycarbonyl group at the amino terminus and the pinacol group at the boron terminus under acidic and heating conditions.

[0011] The borizing agent is selected from boron-10 ester; the dichlorosilane is selected from alkyl dichlorosilane or aryl dichlorosilane.

[0012] As an improvement, the boron-10 ester includes: polyboron-10 ester, ethoxyboron-10 pinacol ester, and isopropoxyboron-10 pinacol ester.

[0013] As an improvement, the synthesis process specifically includes the following steps:

[0014] S1. Add calcium hydride to dry tetrahydrofuran at room temperature;

[0015] S2. At room temperature, a tetrahydrofuran solution of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine is slowly added to the above reaction solution;

[0016] S3. Dichlorosilane is added to the above reaction solution at room temperature;

[0017] S4. Lower the temperature of the reaction system to 0℃, slowly add a tetrahydrofuran solution of isopropyl magnesium chloride and lithium chloride, and react at 0℃ for 7-9 hours;

[0018] S5. Add boriding agent at 0℃, and raise to room temperature, stirring at room temperature for 11-13 hours;

[0019] S6. The extent of the reaction was determined using thin-layer chromatography (TLC);

[0020] S7. Lower the temperature of the reaction system to 0°C and slowly add water to quench the reaction;

[0021] S8. Add ethyl acetate to the reaction mixture from the previous step, collect the organic phase by extraction, and remove the organic solvent under reduced pressure to obtain a liquid residue;

[0022] S9. At room temperature, add acetone and water to the above liquid residue, and then add concentrated hydrochloric acid;

[0023] S10. Heat the reaction system to 55-60℃ and stir for 13-15 hours;

[0024] S11. The reaction was detected as complete using thin-layer chromatography (TLC);

[0025] S12. Cool the concentrated system to below 15°C, adjust the pH of the system with sodium hydroxide solution, and a white solid precipitates out. Filter to obtain a white solid, wash the solid with a small amount of acetone, and dry to obtain the target product.

[0026] As an improvement, in steps S1, S2, and S3, the molar ratio of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine, calcium hydride, and dichlorosilane is 1:2:1.

[0027] As an improvement, the molar ratio of the borizing agent to (S)-N-tert-butoxycarbonyl-4-iodophenylalanine in step S5 is 1.1:1.

[0028] The advantages of this invention are:

[0029] This invention proposes a silane-based protection method for synthesizing (S)-4-dihydroxyboronylphenylalanine. The method uses commercially available amino-terminated (S)-N-tert-butoxycarbonyl-4-iodophenylalanine and reacts with calcium hydride and dichlorosilane to obtain a class of 2-siloxazolidinone-5 intermediates. This intermediate is a cyclic 2-siloxazolidinone-5, the formation of which protects the amino and carboxyl groups of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine. Using isopropyl magnesium chloride·lithium chloride, it undergoes a deiodination magnesiumization reaction at the aryl end, followed by a boronization reaction with a boron-10 ester to generate (S)-N-tert-butoxycarbonyl-4-pinacolboronylphenylalanine. Under strongly acidic and heating conditions, deprotection of the amino-terminated tert-butoxycarbonyl group and the boron-terminated pinacol group yields (S)-4-dihydroxyboronylphenylalanine, i.e., L-BPA.

[0030] In the technical route for producing L-BPA, the main cost comes from the isotopically enriched boron-10 ester raw material. Compared with the traditional method of using boron to protect amino and carboxyl groups, the silicon-based protection method can preferentially react with amino and carboxyl groups to form cyclic 2-siloxazolidinone-5, thus eliminating concerns about the reaction of the amino and carboxyl ends with the boron-10 ester. Therefore, this method can reduce the amount of boron-10 ester used, thereby improving the atom economy of the technical route and reducing the production cost of the drug. In addition, since solid polyboron-10 esters are easy to prepare and store, the synthesis process using solid polyboron-10 esters as raw materials can further reduce the production and operating costs of L-BPA. Attached Figure Description

[0031] Figure 1 This is a schematic diagram of the nuclear reaction that occurs when the boron-10 isotope absorbs thermal neutrons.

[0032] Figure 2 Here are the molecular structures of L-BPA and BSH.

[0033] Figure 3 Schematic diagrams of the structures of (S)-4-iodophenylalanine (I), (S)-4-iodophenylalanine (II) protected at the amino and carboxyl ends, (S)-4-dihydroxyboronylphenylalanine (III) protected at the amino end, and (S)-4-dihydroxyboronylphenylalanine (IV).

[0034] Figure 4 The reaction route for synthesizing (S)-4-dihydroxyboronylphenylalanine using boron-10 alkoxy ester as a protecting group and boronizing agent is shown.

[0035] Figure 5 This is the reaction route diagram for the synthesis of (S)-4-dihydroxyboronylphenylalanine using polyboron-10 ester as a borate in Example 1.

[0036] Figure 6 The reaction route for synthesizing (S)-4-dihydroxyboronylphenylalanine using ethoxyboron-10 acid pinacol ester as a borate reagent is shown in Example 2.

[0037] Figure 7 The reaction route for synthesizing (S)-4-dihydroxyboronylphenylalanine using isopropoxyboron-10 pinacol ester as a borate in Example 3 is shown. Detailed Implementation

[0038] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are some embodiments of the present invention, but not all embodiments.

[0039] This invention discloses a silane-based protection method for synthesizing (S)-4-dihydroxyboronylphenylalanine. The process involves reacting (S)-N-tert-butoxycarbonyl-4-iodophenylalanine, calcium hydride, and dialkylchlorosilane to yield a cyclic 2-siloxazolidinone-5 intermediate. The formation of this intermediate protects the amino and carboxyl groups of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine. Using isopropyl magnesium chloride·lithium chloride allows for deiodination at the aryl end, followed by boronization with a boron-10 ester to generate (S)-N-tert-butoxycarbonyl-4-pinacolboronylphenylalanine. Under strongly acidic and heating conditions, deprotection of the tert-butoxycarbonyl group at the amino end and the pinacol group at the boron end yields (S)-4-dihydroxyboronylphenylalanine, i.e., L-BPA.

[0040] Figure 4 This is a reaction route diagram for the synthesis of L-BPA using traditional methods. Figure 5 , Figure 6 and Figure 7 This is a reaction route diagram for the synthesis of (S)-4-dihydroxyboronylphenylalanine using this method. From... Figure 4 It is known that traditional methods require the use of excess boron-10 alkoxy esters in the synthesis of (S)-4-dihydroxyboronylphenylalanine. This invention proposes a more atom-economical and lower-cost method for synthesizing L-BPA.

[0041] Example 1

[0042] This embodiment discloses a method for synthesizing (S)-4-dihydroxyboronylphenylalanine using polyboron-10 ester as a borate reagent, specifically including the following steps:

[0043] S1. At room temperature (25°C), calcium hydride (2.0 equiv., 840 mg) was added to dry tetrahydrofuran (10 mL).

[0044] S2. At room temperature (25°C), a tetrahydrofuran solution (20 mL) of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine (1.0 equiv., 10 mmol, 3.9 g) was slowly added to the above reaction solution and stirred for 10 minutes. Gas was released and precipitate was formed.

[0045] S3. At room temperature (25°C), dimethyl silicon dichloride (1.0 equiv., 1.3 g, 1.2 mL) was added to the above reaction solution and stirred for 30 minutes.

[0046] S4. Lower the reaction temperature to 0°C, slowly add a tetrahydrofuran solution of isopropyl magnesium chloride and lithium chloride (4.0 equiv., 1.3 mol / L, 30 mL), and react at 0°C for 8 hours. This step is used for the deiodination magnesiumization of silicon-protected (S)-4-dihydroxyboronylphenylalanine.

[0047] S5. Add polyboron-10 ester (B) at 0°C. x pin y The minimum unit molecular weight is 185 (1.1 equiv., 2.0 g), and the mixture is brought to room temperature and stirred for 12 hours.

[0048] S6. The extent of the reaction was determined using thin-layer chromatography (TLC).

[0049] S7. Lower the temperature of the reaction system to 0°C and slowly add 20 mL of water to quench the reaction.

[0050] S8. Add ethyl acetate to the reaction mixture from the previous step, collect the organic phase by extraction, and remove the organic solvent under reduced pressure to obtain a liquid residue.

[0051] S9. At room temperature (25°C), add acetone (20 mL) and water (10 mL) to the above liquid residue, and add concentrated hydrochloric acid (6.0 equiv., 60 mmol, 10 mL).

[0052] S10. Heat the reaction system to 55-60℃ and stir for 14 hours.

[0053] S11. The reaction was detected by thin-layer chromatography (TLC) until it was complete.

[0054] S12. Cool the concentrated system to below 15°C, adjust the pH of the system to about 6.2 with sodium hydroxide solution (4M), a white precipitate will form, filter to obtain a white solid, wash the solid with a small amount of acetone (10mL), dry to obtain the target product.

[0055] In this embodiment, 1.5 g of white solid L-BPA was finally obtained, with a yield of 73%. And using... 1 H, 13 The product was identified using nuclear magnetic resonance imaging (NMR).

[0056] 1 H NMR (400MHz, D2O+DCl): δ7.50(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),4.16(dd , J=5.8, 7.5Hz, 1H), 3.13 (dd, J=5.8, 14.4Hz, 1H), 3.02 (dd, J=7.5, 14.4Hz, 1H).

[0057] 13 C NMR (125MHz, D2O+DCl): δ171.3, 136.9, 134.6, 131.8 (br), 129.2, 54.1, 35.8.

[0058] Example 2

[0059] This embodiment discloses a method for synthesizing (S)-4-dihydroxyboronylphenylalanine using ethoxyboron-10 pinacol ester as a borizing agent, specifically including the following steps:

[0060] S1. At room temperature (25°C), calcium hydride (2.0 equiv., 840 mg) was added to dry tetrahydrofuran (10 mL).

[0061] S2. At room temperature (25°C), a tetrahydrofuran solution (20 mL) of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine (1.0 equiv., 10 mmol, 3.9 g) was slowly added to the above reaction solution and stirred for 10 minutes. Gas was released and precipitate was formed.

[0062] S3. At room temperature (25°C), dimethyl silicon dichloride (1.0 equiv., 1.3 g, 1.2 mL) was added to the above reaction solution and stirred for 30 minutes.

[0063] S4. Lower the temperature of the reaction system to 0℃, slowly add a tetrahydrofuran solution of isopropyl magnesium chloride and lithium chloride (4.0 equiv., 1.3 mol / L, 30 mL), and react at 0℃ for 8 hours.

[0064] S5. At 0°C, add 1.1 equiv., 1.9 g of ethoxyboron-10 acid pinacol ester and bring to room temperature, stirring at room temperature for 12 hours.

[0065] S6. The extent of the reaction was determined using thin-layer chromatography (TLC).

[0066] S7. Lower the temperature of the reaction system to 0°C and slowly add 20 mL of water to quench the reaction.

[0067] S8. Add ethyl acetate to the reaction mixture from the previous step, collect the organic phase by extraction, and remove the organic solvent under reduced pressure to obtain a liquid residue.

[0068] S9. At room temperature (25°C), add acetone (20 mL) and water (10 mL) to the above liquid residue, and add concentrated hydrochloric acid (6.0 equiv., 60 mmol, 10 mL).

[0069] S10. Heat the reaction system to 55-60℃ and stir for 14 hours.

[0070] S11. The reaction was detected by thin-layer chromatography (TLC) until it was complete.

[0071] S12. Cool the concentrated system to below 15°C, adjust the pH of the system to about 6.2 with sodium hydroxide solution (4M), a white precipitate will form, filter to obtain a white solid, wash the solid with a small amount of acetone (10mL), dry to obtain the target product.

[0072] In this embodiment, 1.6 g of white solid L-BPA was finally obtained, with a yield of 78%. And using... 1 The product was identified using H nuclear magnetic resonance imaging.

[0073] 1 H NMR (400MHz, D2O+DCl): δ7.50(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),4.16(dd , J=5.8, 7.5Hz, 1H), 3.13 (dd, J=5.8, 14.4Hz, 1H), 3.02 (dd, J=7.5, 14.4Hz, 1H).

[0074] Example 3

[0075] This embodiment discloses a method for synthesizing (S)-4-dihydroxyboronylphenylalanine using isopropoxyboron-10 pinacol ester as a borizing agent, specifically including the following steps:

[0076] S1. At room temperature (25°C), calcium hydride (2.0 equiv., 840 mg) was added to dry tetrahydrofuran (10 mL).

[0077] S2. At room temperature (25°C), a tetrahydrofuran solution (20 mL) of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine (1.0 equiv., 10 mmol, 3.9 g) was slowly added to the above reaction solution and stirred for 10 minutes. Gas was released and precipitate was formed.

[0078] S3. At room temperature (25°C), dimethyl silicon dichloride (1.0 equiv., 1.3 g, 1.2 mL) was added to the above reaction solution and stirred for 30 minutes.

[0079] S4. Lower the temperature of the reaction system to 0℃, slowly add a tetrahydrofuran solution of isopropyl magnesium chloride and lithium chloride (4.0 equiv., 1.3 mol / L, 30 mL), and react at 0℃ for 8 hours.

[0080] S5. At 0°C, add isopropoxyboron-10 pinacol ester (1.1 equiv., 2.0 g), and bring to room temperature. Stir at room temperature for 12 hours.

[0081] S6. The extent of the reaction was determined using thin-layer chromatography (TLC).

[0082] S7. Lower the temperature of the reaction system to 0°C and slowly add 20 mL of water to quench the reaction.

[0083] S8. Add ethyl acetate to the reaction mixture from the previous step, collect the organic phase by extraction, and remove the organic solvent under reduced pressure to obtain a liquid residue.

[0084] S9. At room temperature (25°C), add acetone (20 mL) and water (10 mL) to the above liquid residue, and add concentrated hydrochloric acid (6.0 equiv., 60 mmol, 10 mL).

[0085] S10. Heat the reaction system to 55-60℃ and stir for 14 hours.

[0086] S11. The reaction was detected by thin-layer chromatography (TLC) until it was complete.

[0087] S12. Cool the concentrated system to below 15°C, adjust the pH of the system to about 6.2 with sodium hydroxide solution (4M), a white precipitate will form, filter to obtain a white solid, wash the solid with a small amount of acetone (10mL), dry to obtain the target product.

[0088] In this embodiment, 1.6 g of white solid L-BPA was finally obtained, with a yield of 78%. And using... 1 The product was identified using H nuclear magnetic resonance imaging.

[0089] 1 H NMR (400MHz, D2O+DCl): δ7.50(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),4.16(dd , J=5.8, 7.5Hz, 1H), 3.13 (dd, J=5.8, 14.4Hz, 1H), 3.02 (dd, J=7.5, 14.4Hz, 1H).

[0090] Example 4

[0091] This embodiment discloses a method for synthesizing (S)-4-dihydroxyboronylphenylalanine using polyboron-10 ester as a borate reagent. In this embodiment, diphenylsilane is selected as the dichlorosilane.

[0092] Specifically, the steps include the following:

[0093] S1. At room temperature (25°C), calcium hydride (2.0 equiv., 840 mg) was added to dry tetrahydrofuran (10 mL).

[0094] S2. At room temperature (25°C), a tetrahydrofuran solution (20 mL) of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine (1.0 equiv., 10 mmol, 3.9 g) was slowly added to the above reaction solution and stirred for 10 minutes. Gas was released and precipitate was formed.

[0095] S3. At room temperature (25°C), diphenyl dichlorosilane (1.0 equiv., 2.5 g) was added to the above reaction solution and stirred for 30 minutes.

[0096] S4. Lower the temperature of the reaction system to 0℃, slowly add a tetrahydrofuran solution of isopropyl magnesium chloride and lithium chloride (4.0 equiv., 1.3 mol / L, 30 mL), and react at 0℃ for 8 hours.

[0097] S5. Add polyboron-10 ester (B) at 0°C. x pin y The minimum unit molecular weight is 185 (1.1 equiv., 2.0 g), and the mixture is brought to room temperature and stirred for 12 hours.

[0098] S6. The extent of the reaction was determined using thin-layer chromatography (TLC).

[0099] S7. Lower the temperature of the reaction system to 0°C and slowly add 20 mL of water to quench the reaction.

[0100] S8. Add ethyl acetate to the reaction mixture from the previous step, collect the organic phase by extraction, and remove the organic solvent under reduced pressure to obtain a liquid residue.

[0101] S9. At room temperature (25°C), add acetone (20 mL) and water (10 mL) to the above liquid residue, and add concentrated hydrochloric acid (6.0 equiv., 60 mmol, 10 mL).

[0102] S10. Heat the reaction system to 55-60℃ and stir for 14 hours.

[0103] S11. The reaction was detected by thin-layer chromatography (TLC) until it was complete.

[0104] S12. Cool the concentrated system to below 15°C, adjust the pH of the system to about 6.2 with sodium hydroxide solution (4M), a white precipitate will form, filter to obtain a white solid, wash the solid with a small amount of acetone (10mL), dry to obtain the target product.

[0105] The specific embodiments of the present invention have been described in detail above, but they are merely examples, and the present invention is not equivalent to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, all equivalent transformations and modifications made without departing from the spirit and scope of the present invention should be covered within the scope of the present invention.

Claims

1. A synthetic process for (S)-4-dihydroxyboronylphenylalanine using a silicon-based protected method, characterized in that, A class of siloxazolidinone intermediates were obtained by reacting (S)-N-tert-butoxycarbonyl-4-iodophenylalanine protected by an amino terminus with calcium hydride and dichlorosilane. The siloxazolidinone intermediate has a cyclic siloxazolidinone structure and can protect the amino and carboxyl groups of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine. The siloxazolidinone intermediate undergoes a deiodinated magnesium reaction at the aryl end using isopropyl magnesium chloride·lithium chloride, followed by a borylation reaction with a borizing agent to generate (S)-N-tert-butoxycarbonyl-4-pinacolborylphenylalanine. (S)-4-dihydroxyboronylphenylalanine was prepared by deprotecting the tert-butoxycarbonyl group at the amino terminus and the pinacol group at the boron terminus under acidic and heating conditions. The boronizing agent is selected from boron-10 ester; the dichlorosilane is an alkyl dichlorosilane or an aryl dichlorosilane, including dimethyl dichlorosilane and diphenyl dichlorosilane.

2. The synthetic process for synthesizing (S)-4-dihydroxyboronylphenylalanine using a silicon-based protected method according to claim 1, characterized in that, The boron-10 esters include: polyboron-10 esters, ethoxyboron-10 pinacol esters, and isopropoxyboron-10 pinacol esters.

3. The synthetic process for synthesizing (S)-4-dihydroxyboronylphenylalanine using a silicon-based protected method according to claim 1, characterized in that, The synthesis process specifically includes the following steps: S1. Add calcium hydride to dry tetrahydrofuran at room temperature; S2. At room temperature, a tetrahydrofuran solution of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine is slowly added to the above reaction solution; S3. Dichlorosilane is added to the above reaction solution at room temperature; S4. Lower the temperature of the reaction system to 0℃, slowly add a tetrahydrofuran solution of isopropyl magnesium chloride and lithium chloride, and react at 0℃ for 7-9 hours; S5. Add boriding agent at 0℃, and raise to room temperature, stirring at room temperature for 11-13 hours; S6. The extent of the reaction was determined using thin-layer chromatography (TLC); S7. Lower the temperature of the reaction system to 0°C and slowly add water to quench the reaction; S8. Add ethyl acetate to the reaction mixture from the previous step, collect the organic phase by extraction, and remove the organic solvent under reduced pressure to obtain a liquid residue; S9. At room temperature, add acetone and water to the above liquid residue, and then add concentrated hydrochloric acid; S10. Heat the reaction system to 55-60℃ and stir for 13-15 hours; S11. The reaction was detected as complete using thin-layer chromatography (TLC); S12. Cool the concentrated system to below 15°C, adjust the pH of the system with sodium hydroxide solution, and a white solid precipitates out. Filter to obtain a white solid, wash the solid with a small amount of acetone, and dry to obtain the target product.

4. The synthetic process for synthesizing (S)-4-dihydroxyboronylphenylalanine using a silicon-based protected method according to claim 3, characterized in that, In steps S1, S2, and S3, the molar ratio of (S)-N-tert-butoxycarbonyl-4-iodophenylalanine, calcium hydride, and dichlorosilane is 1:2:

1.

5. The synthetic process for synthesizing (S)-4-dihydroxyboronylphenylalanine using a silicon-based protected method according to claim 3, characterized in that, The molar ratio of the borizing agent to (S)-N-tert-butoxycarbonyl-4-iodophenylalanine in step S5 is 1.1:1.

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