Preparation method of 4-boric acid-L-phenylalanine

Abstract

The invention relates to the technical field of preparation of medical intermediates, in particular to a preparation method of 4-boric acid-L-phenylalanine. The preparation method comprises the following steps: preparing (S)-2-amino-3-(4-bromophenyl) ethyl propionate; the preparation method comprises the following steps: preparation of (S)-2-amino 3-[4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane-2-yl) phenyl] ethyl propionate; the invention also discloses preparation of the 4-boron-L-phenylalanine. According to the scheme of preparing 4-boric acid group-L-phenylalanine under mild conditions only by using a simple catalyst, the comprehensive yield reaches 60% or above, the reaction conditions are mild, the reaction temperature does not exceed 150 DEG C, reactants are easier to react according to an expected path, the probability of side reaction is reduced, the selectivity and yield of a target product are improved, and the method is suitable for industrial production. And the requirement on the heat resistance of a reaction device is low, and the operation difficulty and the production operation danger are reduced.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate preparation, and in particular to a method for preparing 4-boronic acid-L-phenylalanine. Background Art

[0002] In the field of cancer treatment, traditional methods such as surgery, chemotherapy and radiotherapy often have many limitations when facing complex cancer conditions, making it difficult to achieve accurate and low-damage treatment effects. Boron neutron capture therapy (BNCT) has emerged as a new radiotherapy method with great potential. Its unique treatment principle is to first inject patients with boron-containing drugs to make them highly aggregated in cancer cells, and then use thermal neutrons to irradiate the tumor site. The high-energy particles produced by the fission of boron-10 isotopes after absorbing thermal neutrons can accurately destroy the key structures of cancer cells and reduce damage to surrounding normal tissues. 4-Boron-L-phenylalanine plays a key role in this process. It is one of the commonly used boron carriers in clinical practice and an important boron-containing compound approved for BNCT clinical treatment of cancer.

[0003] Patent CN202310178338.5 and the literature [Nuclear Chemistry and Radiochemistry, 2023, 45, 477] proposed that the structure of 4-boron-L-phenylalanine is similar to natural amino acids such as tyrosine and phenylalanine, which enables it to be integrated into tumor cell targeting peptides using solid phase synthesis technology, effectively solving the problems of poor targeting of boron drugs and low boron loading, and achieving the goal of delivering boron drugs to specific target cells and enriching them in tumor cells. However, its synthesis is not easy, and researchers have been exploring a variety of synthetic routes, such as using palladium-catalyzed cross-coupling reactions (patent CN201310413974.8) or preparing from L-phenylalanine (patent CN202211277248.3), but different methods have their own advantages and disadvantages in terms of reaction conditions, cost, yield and purity.

[0004] In view of the above problems, the present invention provides a method for preparing 4-boron-L-phenylalanine, which does not require the use of expensive iodides, has mild reaction conditions, and can be mass-produced. Summary of the invention

[0005] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for preparing 4-boronic acid-L-phenylalanine.

[0006] A method for preparing 4-boronic acid-L-phenylalanine comprises the following steps:

[0007] S1: Preparation of (S)-2-amino-3-(4-bromophenyl)propionic acid ethyl ester

[0008] S1.1: Weigh 5-6 mol of bromo-L-phenylalanine and dissolve it in 100-110 ml of dichloromethane solution, and place it in an ice-water mixture to maintain the temperature at 0-4°C, then slowly drop twice the molar amount of oxalyl chloride solution of bromo-L-phenylalanine into the solution, and then place it at room temperature 24-26°C to react for 5-8 hours;

[0009] S1.2: After the reaction is completed, 30-35 mol of anhydrous ethanol is added to the solution. A large number of bubbles emerge in the solution. The reaction is continued until no bubbles emerge. The aqueous phase in the reaction solution is removed by centrifugation to obtain a colorless oil, which is the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester.

[0010] S2: Preparation of (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid ethyl ester

[0011] S2.1: Dissolve the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester prepared in step S1, 0.6 equiv of bis-boronic acid pinacol ester, 1-7 mol% of 1,1'-bisdiphenylphosphinoferrocene palladium dichloride and 1-3 equiv of potassium tert-butoxide in 120-150 mL of dimethyl sulfoxide, and continue to introduce nitrogen until the entire atmosphere of the system is replaced by nitrogen, and heat to 80-120° C. for reaction for 2-5 hours;

[0012] S2.2: After the reaction is completed, the reaction product is purified by a rapid purification system to obtain the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionic acid ethyl ester.

[0013] Furthermore, the A liquid of the rapid purification system is a mixture of 5% methanol and 95% water, and the B liquid is a 95% aqueous solution of acetonitrile or methanol.

[0014] S3: Preparation of 4-boron-L-phenylalanine

[0015] S3.1: dissolving the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid ethyl ester prepared in step S2 in a mixed solution of 5 equiv of ethanol, water and sodium hydroxide, and hydrolyzing the mixture at 30-60° C., calculated based on the molar amount of sodium hydroxide, until the compound is completely hydrolyzed;

[0016] S3.2: Slowly add hydrochloric acid solution to the solution until no new precipitate is generated, and obtain 4-boron-L-phenylalanine after filtering and drying.

[0017] Furthermore, the mixed solution of ethanol, water and sodium hydroxide is obtained by mixing ethanol, water and sodium hydroxide in a volume ratio of 2:1:(3-5).

[0018] Furthermore, the concentration of the hydrochloric acid solution is 0.1-0.5M.

[0019] Compared with the prior art, the present invention has at least the following beneficial effects:

[0020] 1. The present invention uses only a simple catalyst to prepare 4-boronic acid-L-phenylalanine under mild conditions, and the comprehensive yield reaches more than 60%. In addition, the reaction conditions are mild, and the reaction temperature does not exceed 150° C. The reactants are more likely to react according to the expected path, reducing the probability of side reactions, improving the selectivity and yield of the target product, and having lower heat resistance requirements for the reactor, reducing the difficulty of operation and the danger of production operations.

[0021] 2. The present invention uses p-bromo-L-phenylalanine as a starting material to prepare 4-boron-L-phenylalanine through esterification, pinacolization and hydrolysis. This scheme does not require the use of expensive iodides, and the preparation method is simple, low-cost, and can be mass-produced, which is suitable for enterprise promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The accompanying drawings, which are incorporated herein and constitute a part of the specification, illustrate embodiments of the present disclosure and, together with the description, further serve to explain the principles of the present disclosure and to enable those skilled in the relevant art to make and use the present disclosure.

[0023] Figure 1 The present invention is a flow chart of a method for preparing 4-boronic acid-L-phenylalanine used in an embodiment of the present invention. DETAILED DESCRIPTION

[0024] The following is a detailed description of a method for preparing 4-boronic acid-L-phenylalanine provided by the present invention in conjunction with the accompanying drawings and specific examples. At the same time, it is explained here that in order to make the embodiments more detailed, the following embodiments are the best and preferred embodiments, and those skilled in the art may also adopt other alternatives to implement some known technologies; and the accompanying drawings are only for more specific description of the embodiments, and are not intended to specifically limit the present invention.

[0025] Embodiment 1:

[0026] A method for preparing 4-boronic acid-L-phenylalanine, as Figure 1 As shown, the following steps are included:

[0027] S1: Preparation of (S)-2-amino-3-(4-bromophenyl)propionic acid ethyl ester

[0028] S1.1: Weigh 5 mol of bromo-L-phenylalanine and dissolve it in 100 ml of dichloromethane solution, and place it in an ice-water mixture to maintain the temperature at 0°C. Then slowly drop twice the molar amount of oxalyl chloride solution of bromo-L-phenylalanine into the solution, and then place it at room temperature 24°C to react for 5 hours;

[0029] S1.2: After the reaction is completed, 30 mol of anhydrous ethanol is added to the solution. A large number of bubbles emerge in the solution. The reaction is continued until no bubbles emerge. The aqueous phase in the reaction solution is removed by centrifugation to obtain a colorless oil, which is the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester.

[0030] S2: Preparation of (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid ethyl ester

[0031] S2.1: Dissolve the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester prepared in step S1, 0.6 equiv of bis-boronic acid pinacol ester, 1 mol% of 1,1'-bisdiphenylphosphinophenoxadiopalladium dichloride and 1 equiv of potassium tert-butoxide in 120 mL of dimethyl sulfoxide, and continue to introduce nitrogen until the entire atmosphere of the system is replaced by nitrogen, and heat to 80°C for reaction for 2 h;

[0032] S2.2: After the reaction is completed, the reaction product is purified by a rapid purification system to obtain the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionic acid ethyl ester. The A liquid of the rapid purification system is a mixture of 5% methanol and 95% water, and the B liquid is a 95% aqueous solution of acetonitrile or methanol.

[0033] S3: Preparation of 4-boron-L-phenylalanine

[0034] S3.1: dissolving the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionic acid ethyl ester prepared in step S2 in a mixed solution of 5 equiv of ethanol, water and sodium hydroxide, wherein the mixed solution of ethanol, water and sodium hydroxide is obtained by mixing ethanol, water and sodium hydroxide in a volume ratio of 2:1:3 based on the molar amount of sodium hydroxide, and hydrolyzing at 30° C. until the compound is completely hydrolyzed;

[0035] S3.2: Slowly add 0.1 M hydrochloric acid solution to the solution until no new precipitate is generated, and obtain 4-boron-L-phenylalanine after filtering and drying.

[0036] The preparation process is as follows:

[0037]

[0038] Embodiment 2:

[0039] A method for preparing 4-boronic acid-L-phenylalanine, as Figure 1 As shown, the following steps are included:

[0040] S1: Preparation of (S)-2-amino-3-(4-bromophenyl)propionic acid ethyl ester

[0041] S1.1: Weigh 5 mol of bromo-L-phenylalanine and dissolve it in 100 ml of dichloromethane solution, and place it in an ice-water mixture to maintain the temperature at 0°C. Then slowly drop twice the molar amount of oxalyl chloride solution of bromo-L-phenylalanine into the solution, and then place it at room temperature 26°C to react for 6 hours;

[0042] S1.2: After the reaction is completed, 30 mol of anhydrous ethanol is added to the solution. A large number of bubbles emerge in the solution. The reaction is continued until no bubbles emerge. The aqueous phase in the reaction solution is removed by centrifugation to obtain a colorless oil, which is the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester.

[0043] S2: Preparation of (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid ethyl ester

[0044] S2.1: Dissolve the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester prepared in step S1, 0.6 equiv of bis-boronic acid pinacol ester, 3 mol% of 1,1'-bisdiphenylphosphinoferrocene palladium dichloride and 2 equiv of potassium tert-butoxide in 130 mL of dimethyl sulfoxide, and continue to introduce nitrogen until the entire atmosphere of the system is replaced by nitrogen, and heat to 100° C. for reaction for 3 h;

[0045] S2.2: After the reaction is completed, the reaction product is purified by a rapid purification system to obtain the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionic acid ethyl ester. The A liquid of the rapid purification system is a mixture of 5% methanol and 95% water, and the B liquid is a 95% aqueous solution of acetonitrile or methanol.

[0046] S3: Preparation of 4-boron-L-phenylalanine

[0047] S3.1: dissolving the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid ethyl ester prepared in step S2 in a mixed solution of 5 equiv of ethanol, water and sodium hydroxide, wherein the mixed solution of ethanol, water and sodium hydroxide is obtained by mixing ethanol, water and sodium hydroxide in a volume ratio of 2:1:3 based on the molar amount of sodium hydroxide, and hydrolyzing at 40° C. until the compound is completely hydrolyzed;

[0048] S3.2: Slowly add 0.2 M hydrochloric acid solution to the solution until no new precipitate is generated, and obtain 4-boron-L-phenylalanine after filtering and drying.

[0049] Embodiment 3:

[0050] A method for preparing 4-boronic acid-L-phenylalanine, as Figure 1 As shown, the following steps are included:

[0051] S1: Preparation of (S)-2-amino-3-(4-bromophenyl)propionic acid ethyl ester

[0052] S1.1: Weigh 5 mol of bromo-L-phenylalanine and dissolve it in 100 ml of dichloromethane solution, and place it in an ice-water mixture to maintain the temperature at 4°C. Then slowly drop twice the molar amount of oxalyl chloride solution of bromo-L-phenylalanine into the solution, and then place it at room temperature 24°C to react for 7 hours;

[0053] S1.2: After the reaction is completed, 30 mol of anhydrous ethanol is added to the solution. A large number of bubbles emerge in the solution. The reaction is continued until no bubbles emerge. The aqueous phase in the reaction solution is removed by centrifugation to obtain a colorless oil, which is the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester.

[0054] (S)-2-amino-3-(4-bromophenyl)propionic acid ethyl ester:

[0055] 1H NMR (40MHz, CDCl3) δ7.41(d,J=8.4Hz,2H),7.07(d,J=8.4Hz,2H),4.15(q,J=7.1Hz,2H),3.66(dd,J=7.7,5.4Hz,1H),3.01(dd,J=13.6,5.4Hz,1H),2 .81(dd,J=13.6,7.8Hz,1H),1.47(bs,2H),1.23(t,J=7.1Hz,3H); 13CNMR( 75MHz, CDCl3) δ174.8,136.3,131.5,131.0,120.7,61.0,55.6,40.4,14.2.

[0056] S2: Preparation of (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid ethyl ester

[0057] S2.1: Dissolve the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester prepared in step S1, 0.6 equiv of bis-boronic acid pinacol ester, 5 mol% of 1,1'-bisdiphenylphosphinoferrocene palladium dichloride and 3 equiv of potassium tert-butoxide in 140 mL of dimethyl sulfoxide, and continue to introduce nitrogen until the entire atmosphere of the system is replaced by nitrogen, and heat to 120° C. for reaction for 3 h;

[0058] S2.2: After the reaction is completed, the reaction product is purified by a rapid purification system to obtain the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionic acid ethyl ester. The A liquid of the rapid purification system is a mixture of 5% methanol and 95% water, and the B liquid is a 95% aqueous solution of acetonitrile or methanol.

[0059] S3: Preparation of 4-boron-L-phenylalanine

[0060] S3.1: dissolving the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionic acid ethyl ester prepared in step S2 in a mixed solution of 5 equiv of ethanol, water and sodium hydroxide, wherein the mixed solution of ethanol, water and sodium hydroxide is obtained by mixing ethanol, water and sodium hydroxide in a volume ratio of 2:1:4 based on the molar amount of sodium hydroxide, and hydrolyzing at 50° C. until the compound is completely hydrolyzed;

[0061] S3.2: Slowly add 0.3 M hydrochloric acid solution to the solution until no new precipitate is generated, and obtain 4-boron-L-phenylalanine after filtering and drying.

[0062] Embodiment 4:

[0063] A method for preparing 4-boronic acid-L-phenylalanine, as Figure 1 As shown, the following steps are included:

[0064] S1: Preparation of (S)-2-amino-3-(4-bromophenyl)propionic acid ethyl ester

[0065] S1.1: Weigh 5 mol of bromo-L-phenylalanine and dissolve it in 100 ml of dichloromethane solution, and place it in an ice-water mixture to maintain the temperature at 0°C. Then slowly drop twice the molar amount of oxalyl chloride solution of bromo-L-phenylalanine into the solution, and then place it at room temperature 24°C to react for 8 hours;

[0066] S1.2: After the reaction is completed, 30 mol of anhydrous ethanol is added to the solution. A large number of bubbles emerge in the solution. The reaction is continued until no bubbles emerge. The aqueous phase in the reaction solution is removed by centrifugation to obtain a colorless oil, which is the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester.

[0067] S2: Preparation of (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid ethyl ester

[0068] S2.1: Dissolve the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester prepared in step S1, 0.6 equiv of bis-boronic acid pinacol ester, 7 mol% of 1,1'-bisdiphenylphosphinoferrocene palladium dichloride and 3 equiv of potassium tert-butoxide in 150 mL of dimethyl sulfoxide, and continue to introduce nitrogen until the entire atmosphere of the system is replaced by nitrogen, and heat to 120°C for reaction for 5 hours;

[0069] S2.2: After the reaction is completed, the reaction product is purified by a rapid purification system to obtain the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionic acid ethyl ester. The A liquid of the rapid purification system is a mixture of 5% methanol and 95% water, and the B liquid is a 95% aqueous solution of acetonitrile or methanol.

[0070] S3: Preparation of 4-boron-L-phenylalanine

[0071] S3.1: dissolving the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionic acid ethyl ester prepared in step S2 in a mixed solution of 5 equiv of ethanol, water and sodium hydroxide, wherein the mixed solution of ethanol, water and sodium hydroxide is obtained by mixing ethanol, water and sodium hydroxide in a volume ratio of 2:1:4 based on the molar amount of sodium hydroxide, and hydrolyzing at 60°C until the compound is completely hydrolyzed;

[0072] S3.2: Slowly add 0.5 M hydrochloric acid solution to the solution until no new precipitate is generated, and obtain 4-boron-L-phenylalanine after filtering and drying.

[0073] The yields of the reaction products ((S)-2-amino-3-(4-bromophenyl)ethyl propionate, (S)-2-amino-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl propionate and 4-boron-L-phenylalanine) in Examples 1-4 were statistically analyzed as shown in Table 1.

[0074] Table 1: Reaction product yield (%)

[0075]

[0076] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A method for preparing 4-boronic acid-L-phenylalanine, characterized in that: The steps include: S1: Preparation of (S)-2-amino-3-(4-bromophenyl)propionic acid ethyl ester Weigh bromo-L-phenylalanine and dissolve it in a dichloromethane solution, then slowly drop oxalyl chloride solution into the solution for reaction. After the reaction is completed, add anhydrous ethanol into the solution, a large number of bubbles emerge in the solution, and continue the reaction until no bubbles emerge. Centrifuge to remove the aqueous phase liquid in the reaction solution to obtain a colorless oil, which is the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester; S2: Preparation of (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid ethyl ester The intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester prepared in step S1, bis-boronic acid pinacol ester, 1,1'-bisdiphenylphosphinoferrocene palladium dichloride and potassium tert-butoxide are dissolved in dimethyl sulfoxide, and nitrogen is continuously introduced until the entire atmosphere of the system is replaced by nitrogen, and the reaction is heated. After the reaction is completed, the reaction product is purified by a rapid purification system to obtain the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionic acid ethyl ester; S3: Preparation of 4-boron-L-phenylalanine The intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionic acid ethyl ester prepared in step S2 is dissolved in a mixed solution of ethanol, water and sodium hydroxide, and hydrolyzed until the compound is completely hydrolyzed. A hydrochloric acid solution is slowly added to the solution, and 4-boron-L-phenylalanine is obtained after filtering and drying.

2. The method for preparing 4-boronic acid-L-phenylalanine according to claim 1, characterized in that: Step S1: Preparation of (S)-2-amino-3-(4-bromophenyl)ethyl propionate, comprising the following steps: S1.1: Weigh 5-6 mol of bromo-L-phenylalanine and dissolve it in 100-110 ml of dichloromethane solution, and place it in an ice-water mixture to maintain the temperature at 0-4°C, then slowly drop twice the molar amount of oxalyl chloride solution of bromo-L-phenylalanine into the solution, and then place it at room temperature 24-26°C to react for 5-8 hours; S1.2: After the reaction is completed, 30-35 mol of anhydrous ethanol is added to the solution. A large number of bubbles emerge in the solution. The reaction is continued until no bubbles emerge. The aqueous phase in the reaction solution is removed by centrifugation to obtain a colorless oil, which is the intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester.

3. The method for preparing 4-boronic acid-L-phenylalanine according to claim 2, characterized in that: Step S2: Preparation of (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl propionate, comprising the following steps: S2.1: The intermediate (S)-2-amino-3-(4-chlorophenyl)propionic acid ethyl ester prepared in step S1, 0.6 equiv of bis-boronic acid pinacol ester, 1-7 mol% of 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride and 1- 3 equiv of potassium tert-butoxide is dissolved in 120-150 mL of dimethyl sulfoxide, and nitrogen is continuously introduced until the entire atmosphere of the system is replaced by nitrogen, and heated to 80-120°C for reaction for 2-5 hours; S2.2: After the reaction is completed, the reaction product is purified by a rapid purification system to obtain the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propionic acid ethyl ester.

4. The method for preparing 4-boronic acid-L-phenylalanine according to claim 3, characterized in that: In step S2.2, liquid A of the rapid purification system is prepared by mixing 5% methanol and 95% water, and liquid B is a 95% aqueous solution of acetonitrile or methanol.

5. The method for preparing 4-boronic acid-L-phenylalanine according to claim 3, characterized in that: Step S34-the preparation of boron-L-phenylalanine comprises the following steps: S3.1: dissolving the intermediate (S)-2-amino 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoic acid ethyl ester prepared in step S2 in a mixed solution of 5 equiv of ethanol, water and sodium hydroxide, and hydrolyzing the mixture at 30-60° C., calculated based on the molar amount of sodium hydroxide, until the compound is completely hydrolyzed; S3.2: Slowly add hydrochloric acid solution to the solution until no new precipitate is generated, and obtain 4-boron-L-phenylalanine after filtering and drying.

6. The method for preparing 4-boronic acid-L-phenylalanine according to claim 5, characterized in that: The mixed solution of ethanol, water and sodium hydroxide in step S3.1 is obtained by mixing ethanol, water and sodium hydroxide in a volume ratio of 2:1:(3-5).

7. The method for preparing 4-boronic acid-L-phenylalanine according to claim 5, characterized in that: The concentration of the hydrochloric acid solution in step S3.2 is 0.1-0.5M.

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