Process for the preparation of 4-borono-phenylalanine

Abstract

This invention relates to a method for preparing 4-dihydroxyboronylphenylalanine (BPA) from 4-iodophenylalanine, wherein all functional groups of the amino acid are protected by a benzyl protection method, and the method uses isopropyl magnesium halide stabilized by a complexing base, followed by the condensation of the resulting Grignard reagent with a borate ester. The final reaction step, namely the catalytic hydrogenolysis or transfer hydrogenolysis of the protecting group on the amino acid, occurs after the hydrolysis of the borate ester group.

Description

Technical Field

[0001] This invention relates to a method for preparing 4-dihydroxyborylphenylalanine (BPA), particularly containing... 10 The product of the B isotope and the L-phenylalanine configuration. The compound is known; containing... 10 Derivatives of boron isotopes have been used as cancer treatment drugs in so-called boron neutron capture therapy (BNCT). Background Technology

[0002] 4-Dihydroxyborylphenylalanine (BPA) is a borate-modified amino acid with a specific affinity for tumors. 10 BPA, an isotope of B, is a compound used clinically for BNCT, in which tumor cells are degraded after neutron irradiation.

[0003] In order to find a feasible synthetic method for 4-dihydroxyborylphenylalanine, several methods using organometallic intermediates have been disclosed.

[0004] EP 2865682B1 by Kuen-Wang et al. discloses a method for synthesizing 4-dihydroxyboryl-phenylalanine by reacting N-protected 4-halophenylalanine, a borate agent, and an organolithium compound.

[0005] Li et al.'s WO 2017 / 028751 discloses a method for synthesizing 4-dihydroxyboryl-phenylalanine by reacting N-protected 4-halophenylalanine with a borate, a Grignard reagent, and bis(2-methyl-aminoethyl) ether. The method is characterized by its simple process without complex multi-step procedures. Summary of the Invention

[0006] Technical issues

[0007] The main objective of this invention is to synthesize 4-dihydroxyboryl-phenylalanine with significant technical advantages, such as operation under mild reaction conditions, saving reagents and catalysts, minimizing the amount of byproducts, and significantly reducing the purification required to obtain pharmaceutical products.

[0008] Technical solutions to the problem

[0009] When investigating borylation in a given reaction with a Grignard reagent, the inventors surprisingly discovered even better conditions for borylation and protection of all functional groups. Conditions for the synthesis of boric acid after protecting all functional groups of the amino acid have been found, and finally, conditions for the catalytic removal of protecting groups from the amino acid configuration have also been discovered.

[0010] The present invention will be mainly mentioned below.

[0011] (Item 1)

[0012] A method for preparing 4-dihydroxyboronylphenylalanine from 4-iodophenylalanine, characterized in that:

[0013] In the first reaction step, the carboxyl functional group of 4-iodophenylalanine is protected as a benzyl ester, and the amino group of 4-iodophenylalanine is protected as a dibenzyl derivative or a benzyloxycarbonyl derivative. Then, by reacting with isopropyl magnesium halide stabilized with a complexing base, the iodine in the resulting protected 4-iodophenylalanine is replaced by the magnesium halide, yielding the 4-magnesium halide of the protected phenylalanine.

[0014] In the second reaction step, the 4-magnesium halide of the protected phenylalanine obtained in the first reaction step is substituted with a borate ester of the general formula B(OR)3, wherein R is an aliphatic alkyl, phenyl, or benzyl group having 1 to 10 carbon atoms. The resulting borate ester group is then hydrolyzed to give the protected 4-dihydroxyborylphenylalanine.

[0015] In the third reaction step, the protected 4-dihydroxyborylphenylalanine obtained in the second reaction step is deprotected by catalytic hydrogenolysis or transfer hydrogenolysis using a Pd catalyst, and then the reaction mixture is precipitated with a base to obtain 4-dihydroxyborylphenylalanine.

[0016] (Item 2)

[0017] According to the method described in item 1, wherein,

[0018] In the first reaction step, the protected 4-iodophenylalanine is reacted with isopropyl magnesium halide stabilized with a complexing base in an ether medium at a temperature of -20°C to 20°C, with a molar ratio of magnesium isopropyl magnesium halide to the protected 4-iodophenylalanine of 1 to 1.5, to obtain a 4-magnesium halide of the protected phenylalanine, wherein the halide is a chloride or bromide, and the complexing base is selected from bis[2-(N,N-dimethylamino)ethyl] ether, N,N,N',N'-tetramethylethylenediamine, 1,4-diazabicyclo[2,2,2]octane, N-methylmorpholine, and N,N,N',N',N'-pentamethyldiethylenetriamine.

[0019] In the second reaction step, the 4-magnesium halide is substituted with the boronic ester at a temperature of -70°C to 0°C and a molar ratio of the boronic ester to the 4-magnesium halide of the protected phenylalanine of 1 to 2. Subsequently, the resulting boronic ester group is hydrolyzed in an aqueous acidic medium at a temperature of 0°C to 50°C to obtain the protected 4-dihydroxyboronic phenylalanine.

[0020] In the third reaction step, the protecting group is catalytically hydrogenolytically cracked by a Pd catalyst in an amount of 1% to 150% by weight, based on the protected 4-dihydroxyborylphenylalanine, at a hydrogen pressure of 0.1 MPa to 10 MPa and a temperature of 15°C to 120°C, in an aqueous alcoholic medium, in the presence of an organic or inorganic acid, and the reaction mixture is precipitated by adjusting the pH of the reaction mixture to 5 to 8 with an alkali at a temperature of 0°C to 50°C to obtain 4-dihydroxyborylphenylalanine.

[0021] Alternatively, transfer hydrogenation can be performed when a hydrogen donor is used instead of hydrogen gas.

[0022] (Item 3)

[0023] According to the method described in claim 1 or claim 2, the complexing base in the first reaction step is bis[2-(N,N-dimethylamino)ethyl] ether.

[0024] (Item 4)

[0025] According to the method of any one of claims 1 to 3, wherein the substitution reaction in the first reaction step is carried out under the following conditions: a temperature of -5°C to 5°C, in a tetrahydrofuran medium, and a molar ratio of magnesium isopropyl halide to the protected 4-iodophenylalanine of 1.2.

[0026] (Item 5)

[0027] According to the method of any one of items 1 to 4, wherein the borate ester used in the second reaction step is methyl ester or ethyl ester, and the reaction is carried out at a temperature of -25°C to -15°C.

[0028] (Item 6)

[0029] According to the method of any one of claims 1 to 5, wherein, in the second reaction step, the ratio of the borate ester to the 4-magnesium halide of the protected phenylalanine is 1.5.

[0030] (Item 7)

[0031] According to any one of claims 1 to 6, in the second reaction step, the aqueous acid medium is 3M to 5M hydrochloric acid at a temperature of 5°C to 25°C.

[0032] (Item 8)

[0033] According to any one of claims 1 to 7, the catalytic hydrogenolysis is carried out under the following conditions: the Pd catalyst is carbon-supported palladium, the amount of which is 1 to 10% by weight based on the protected 4-dihydroxyborylphenylalanine, the temperature is 30°C to 70°C, and the hydrogen pressure is 0.5 MPa to 2 MPa.

[0034] (Item 9)

[0035] According to any one of items 1 to 8, the transfer hydrogenolysis in the third reaction step preferably uses 20% to 50% by weight of silicon dioxide-supported palladium (Pd content of 20%) and preferably uses 7% to 15% molar excess formic acid, and is carried out at 50°C to 70°C.

[0036] (Item 10)

[0037] According to any one of claims 1 to 9, the deprotection in the third reaction step is carried out under the following conditions: in a reaction medium containing 20% ​​to 50% vol% water in aqueous ethanol, in the presence of hydrochloric acid, the amount of which is 0.5 to 3, preferably 1 to 2, molar equivalents of HCl based on the protected 4-dihydroxyborylphenylalanine.

[0038] (Item 11)

[0039] According to any one of items 1 to 10, the precipitation in the third reaction step is carried out under the following conditions: pH 6 to 7, temperature 5°C to 15°C, and the use of NaOH or KOH.

[0040] (Item 12)

[0041] According to the method of any one of claims 1 to 11, wherein, after the second reaction step, the generated 4-dihydroxyborylphenylalanine is further purified by extraction with an ester solvent, particularly with ethyl acetate, and washed with sodium bicarbonate solution and water, and further purified with activated carbon if necessary, to obtain purified protected 4-dihydroxyborylphenylalanine.

[0042] (Item 13)

[0043] The method according to any one of claims 1 to 12, wherein the method uses L-configured phenylalanine and / or is rich in... 10 The boron compounds of the B isotope were used.

[0044] (Item 14)

[0045] A protected 4-magnesium halide of phenylalanine as shown in Formula 2, which serves as an intermediate in the preparation of 4-dihydroxyborylphenylalanine.

[0046] [Chemical Formula 1]

[0047]

[0048] Where R 1and R 2 It is benzyl, or R 1 It is a benzyloxycarbonyl group, R 2 H is a radical; Bn is a benzyl group; X is Cl or Br.

[0049] (Item 15)

[0050] A protected 4-dihydroxyborylphenylalanine as shown in Formula 3, which serves as an intermediate in the preparation of 4-dihydroxyborylphenylalanine.

[0051] [Chemical Formula 2]

[0052]

[0053] Where R 1 and R 2 It is benzyl, or R 1 It is a benzyloxycarbonyl group, R 2 H; Bn is benzyl; R 3 It is a C1 to C10 alkyl, phenyl or benzyl group.

[0054] The effects of the invention

[0055] According to the invention as a whole, the described reaction sequence offers significant technical advantages, such as operation under mild reaction conditions, savings in reagents and catalysts, minimization of byproduct amounts, and a significant reduction in the purification required to obtain pharmaceutical products. The yield of the obtained product is high. Attached Figure Description

[0056] none Invention Details

[0058] Before implementing the method of the present invention, the functional groups of 4-iodophenylalanine must be adequately protected, particularly sterically. The carboxyl group is protected as a benzyl ester group, and the amino group is protected as a dibenzyl (Bn) or benzyloxycarbonyl (Z) derivative, as shown in Formula 1 of the protected 4-iodophenylalanine below:

[0059] [Chemical Formula 3]

[0060]

[0061] Where R 1 and R 2 It is benzyl, or R 1 It is a benzyloxycarbonyl group, R 2 H is present; Bn is benzyl.

[0062] The protection of amino acid groups by benzylation is previously known: M.T. Reetz, Tetrahedron Asymmetry, 1990, 1, (6), 375; H. Nakamura et al., Bulletin of the Chemical Society of Japan, 2000, 73, 231.

[0063] When protected 4-iodophenylalanine 1 When the iodine is replaced by a MgX group on the nucleus, slightly low temperature conditions must be selected, and a complexing agent for isopropyl magnesium halide (iPrMgX) must be used; the reaction produces the protected 4-magnesium halide of phenylalanine as shown in Formula 2, which, as an intermediate product, is also part of this invention.

[0064] [Chemical Formula 4]

[0065]

[0066] Where R 1 and R 2 It is benzyl, or R 1 It is a benzyloxycarbonyl group, R 2 H is a radical; Bn is a benzyl group; X is Cl or Br.

[0067] Grignard reagents 2 The reaction with borate esters needs to be carried out at a temperature preferably below -10°C. With the above Grignard reagents... 2 Similarly, the esters (boronic acid esters) of boric acid shown in Formula 3 below have not been previously described:

[0068] [Chemical Formula 5]

[0069]

[0070] Where R 1 and R 2 It is benzyl, or R 1 It is a benzyloxycarbonyl group, R 2 H; Bn is benzyl; R 3 It is a C1 to C10 alkyl, phenyl or benzyl group.

[0071] These compounds were not separated in the method of this invention. Boronate esters 3 The ester bonds in the ester are hydrolyzed under laboratory conditions by previously known methods, such as with concentrated acids (e.g., hydrochloric acid).

[0072] In obtaining boric acid 4Subsequently (see Scheme 1 below), the protective benzyl or benzyloxycarbonyl groups on amino acids are removed by catalytic hydrogenation or transfer hydrogenation on a Pd catalyst under commonly used catalytic conditions, i.e., with a catalyst-to-substrate weight ratio of a few percent or tens of percent relative to the substrate. 4-Dihydroxyborylphenylalanine (BPA) has already been achieved. 5 It achieved a high yield of over 80% and even high purity.

[0073] [Chemical Formula 6]

[0074] Option 1:

[0075]

[0076] Where R 1 and R 2 It is benzyl, or R 1 It is a benzyloxycarbonyl group, R 2 H; Bn is benzyl; R 3 It is a C1 to C10 alkyl, phenyl, or benzyl group; X is Cl or Br.

[0077] The subject of this invention is a protected 4-iodophenylalanine. 1 Preparation of 4-dihydroxyborylphenylalanine 5 The method wherein the carboxyl functional group is protected as a benzyl ester, and the amino group is protected as a benzyloxycarbonyl group or preferably as a dibenzyl derivative, wherein in the first reaction step, the protected 4-iodophenylalanine is protected by reacting with isopropyl magnesium halide stabilized by a complexing base. 1 The iodine in the phenylalanine is replaced by magnesium halide, yielding the protected 4-magnesium halide of phenylalanine. 2 .

[0078] The halogen in isopropyl magnesium halide is chlorine or bromine, preferably chlorine. The complexing base is, for example, bis[2-(N,N-dimethylamino)ethyl] ether, TMEDA (N,N,N',N'-tetramethylethylenediamine), DABCO (1,4-diazabicyclo[2.2.2]octane), NMM (N-methylmorpholine), N,N,N',N',N'-pentamethyldiethylenetriamine, preferably bis[2-(N,N-dimethylamino)ethyl] ether.

[0079] The reaction in the first reaction step is carried out under the following conditions: in an ether medium, preferably in tetrahydrofuran, at a temperature of -20°C to 20°C, preferably -5°C to 5°C, and the molar ratio of iPrMgX to the substrate is 1 to 1.5, preferably 1.2.

[0080] The phenylalanine protected in the second reaction step 2The 4-magnesium halide group is replaced by a borate group, thereby forming a borate ester derivative. 3 This is done using a borate ester of formula B(OR)3, where R in B(OR)3 is an aliphatic alkyl, phenyl, or benzyl group having 1 to 10 carbon atoms, preferably methyl or ethyl. The temperature used is low, for example -70°C to 0°C, preferably -25°C to -15°C. The borate ester reacts with the substrate... 2 The molar ratio is 1 to 2, preferably 1.5.

[0081] In the second reaction step, the compound is immediately followed by... 3 The ester group of the boric acid functional group is hydrolyzed, preferably without separation, at a temperature of 0°C to 50°C, preferably 5°C to 25°C, preferably using an aqueous acid with a concentration of 3 to 5 mol / L, preferably hydrochloric acid. The crude product is the protected 4-dihydroxyborylphenylalanine. 4 It is typically extracted with an ester solvent, preferably ethyl acetate, and purified by washing with a solution of sodium bicarbonate and water. If desired, it can be thoroughly purified, for example, with activated carbon, and concentrated to give an oily product, namely purified protected 4-dihydroxyborylphenylalanine. 4 Or, in other words, 4-dihydroxyboryl-N,N-dibenzyl (or benzyloxycarbonyl)phenylalanine benzyl ester, with a yield as high as 90% of the theoretical value.

[0082] In the third reaction step, the protected 4-dihydroxyborylphenylalanine obtained in the second reaction step is obtained through catalytic hydrogenolysis or transfer hydrogenolysis. 4 The benzyl and benzyloxycarbonyl protecting groups are removed from the amino acid configuration. The catalyst used contains palladium, for example, Pearlman catalyst, palladium supported on alumina, preferably Pd / C (palladium supported on activated carbon) or Pd / SiO2 (palladium supported on silica). The Pd content on the support is typically 1-20% by weight. The amount of catalyst depends on the purity of the feedstock, the desired reaction rate, and the temperature. Typically, the amount of catalyst is in the range of 1-150% by weight based on the hydrogenated material; however, the method of the present invention preferably uses only 1-10% by weight, and the reaction time is only a few hours. The debenzylation temperature can be selected from 15°C to 120°C, preferably 30°C-70°C. The hydrogen pressure is 0.1 MPa to 10 MPa, preferably higher than atmospheric pressure, for example 0.5 MPa to 2 MPa. The hydrogenolysis medium consists of an alcohol, preferably an aqueous alcohol with a water content of 20% to 50% by volume. The medium used is acidic due to the addition of inorganic acids (sulfuric acid, phosphoric acid, preferably hydrochloric acid), but organic acids (acetic acid, methanesulfonic acid, toluenesulfonic acid, benzoic acid, trifluoroacetic acid) can also be used. The amount of acid used is relative to the substrate, namely the protected 4-dihydroxyborylphenylalanine. 4 The amount is 0.5 to 3 molar equivalents, preferably 1 to 2 molar equivalents.

[0083] Alternatively, transfer hydrogenation can be used to remove the protecting group. Transfer hydrogenation has been successfully carried out using a suitable hydrogen donor (preferably formic acid) and with palladium supported on silica as a catalyst.

[0084] Following hydrogenolysis, the crude product 4-dihydroxyborylphenylalanine is prepared by precipitation with an alkali at pH 5 to 8, preferably pH 6 to 7, and at a temperature of 0 to 50°C, preferably 5 to 15°C. 5 The preferred base is NaOH or KOH. The product need not be dried; it is preferably further purified, for example, by repeated precipitation from the hydrochloride salt.

[0085] The method can be used for racemic phenylalanine derivatives, as well as D-type, L-type, and different types. 10 The product is enriched to a certain degree by B isotope concentration. The method of this invention provides the final product in high yield, when compared with the precursor. 1 The yield was calculated to be 80%, and the method has low labor intensity, thus resulting in high production efficiency. Boric acid. 4 The synthesis of the precursor under normal conditions can be carried out in a short time with a high selectivity of over 80%. 1 The process is carried out in situ, and after optimized hydrogenolysis, the final product BPA is generated. 5 . Detailed Implementation

[0086] Example 1: 4-Dihydroxyboryl-N,N-dibenzyl-L-phenylalanine benzyl ester 4

[0087] 685g (1.146mol) of 4-iodo-N,N-dibenzyl-L-phenylalanine benzyl ester hydrochloride 1 It was dissolved in 800 ml of dichloromethane and converted to a base by extraction with 5% sodium bicarbonate solution. The organic phase was concentrated and then diluted with 540 ml of anhydrous THF.

[0088] A 6-liter flask was filled with 750 mL of THF, 260 mL of bis[2-(N,N-dimethylamino)ethyl] ether (1.38 mol), and 690 mL of 2M THF solution of isopropyl magnesium chloride, and stirred at 10–15 °C for 30 min. The reaction mixture was then cooled to 0 °C, and a THF solution of 4-iodo-N,N-dibenzyl-L-phenylalanine benzyl ester was added. The mixture was stirred at 0–5 °C until the reaction was complete as determined by HPLC. The reaction mixture was then cooled to -20 °C, and 190 mL of trimethyl borate (1.72 mol) was added. The reaction mixture was heated to laboratory temperature over 2 hours and stirred for another 2 hours. The reaction was neutralized with 1400 mL of 4M HCl to complete the reaction. The organic phase was extracted with 680 mL of ethyl acetate and washed with 550 mL of 5% sodium bicarbonate solution and 2 × 400 mL of water. After concentration, 580g of 4-dihydroxyboryl-N,N-dibenzyl-L-phenylalanine benzyl ester, a yellow oil, was obtained.

[0089] Example 2: 4-Dihydroxyboryl-L-phenylalanine 5 BPA

[0090] The product contains 100.9 g (0.21 mol) of 4-dihydroxyboryl-N,N-dibenzyl-L-phenylalanine benzyl ester. 4 The concentrate was dissolved in 280 ml of ethanol, to which 43 ml of softened water and 37 ml of 35% HCl (0.42 mol) were added, and the solution was placed in an autoclave. Hydrogenolysis was carried out via Pd / C (10 g, 5% Pd, 50% water) catalysis at a hydrogen pressure of 0.5–1.2 MPa and a temperature up to 60 °C, with the reaction monitored by HPLC. After the reaction was complete, the catalyst was separated by filtration, and the filtrate was precipitated by adjusting the pH to 6–7 with 30% NaOH aqueous solution. After cooling to 0–5 °C, BPA crystals were filtered off, with a yield of 84% of the theoretical value. Purification was then performed by precipitation from the hydrochloride solution with 30% NaOH aqueous solution. The purified yield was 91%, the HPLC purity was 99.0%, and the L-phenylalanine content was less than 1%.

[0091] Example 3:

[0092] 4-Dihydroxyboryl-N,N-dibenzyl-L-phenylalanine benzyl ester 41.2 g of catalyst Pd / SiO2 (20% Pd, 55% water) was added to a solution of 4.3 g (0.009 mol) in 25 mL of ethanol. The mixture was heated to 50-70 °C, and formic acid (4.5 mL) in 20 mL of ethanol was added over 15 minutes. The reaction mixture was stirred at 50-70 °C for 3 hours, then cooled to room temperature. The catalyst was filtered off, and the resulting solution was neutralized to pH 6-7 with sodium hydroxide while stirring and maintaining the temperature at 5-15 °C. After cooling to 0-5 °C, BPA crystals were filtered off, with a yield of 80% of the theoretical value.

[0093] Industrial applicability

[0094] This invention relates to a method for preparing 4-dihydroxyboronylphenylalanine for boron neutron capture therapy (BNCT) in tumor treatment, particularly having... 10 A new approach to the product of B isotope and L-phenylalanine configuration.

[0095] The novel synthesis of 4-dihydroxyborylphenylalanine, utilizing a Grignard reaction with benzyl protection of the functional group and an optimized protecting group removal procedure, is more economical, less labor-intensive, and provides high yields. According to the invention as a whole, the reaction sequence offers significant technical advantages, such as operation under mild reaction conditions, savings in reagents and catalysts, and minimization of byproducts. The overall separation yield is in the range of 70-80%, and the purity (99% HPLC) is suitable for pharmaceutical use.

Claims

1. A method for preparing 4-dihydroxyboronylphenylalanine from 4-iodophenylalanine, characterized in that: In the first reaction step, the carboxyl functional group of 4-iodophenylalanine is protected as a benzyl ester, and the amino group of 4-iodophenylalanine is protected as a dibenzyl or benzyloxycarbonyl derivative. Then, by reacting with isopropyl magnesium halide stabilized with a complexing base, the iodine in the resulting protected 4-iodophenylalanine is replaced by the magnesium halide, yielding the 4-magnesium halide of the protected phenylalanine. In the second reaction step, the 4-magnesium halide of the protected phenylalanine obtained in the first reaction step is substituted with a borate ester of the general formula B(OR)3, wherein R is an aliphatic alkyl, phenyl, or benzyl group having 1 to 10 carbon atoms. The resulting borate ester group is then hydrolyzed to give the protected 4-dihydroxyborylphenylalanine. In the third reaction step, the protected 4-dihydroxyborylphenylalanine obtained in the second reaction step is deprotected by catalytic hydrogenolysis or transfer hydrogenolysis using a Pd catalyst, and then the reaction mixture is precipitated with a base to obtain 4-dihydroxyborylphenylalanine.

2. The method according to claim 1, wherein, In the first reaction step, the protected 4-iodophenylalanine is reacted with isopropyl magnesium halide stabilized with a complexing base in an ether medium at a temperature of -20°C to 20°C, with a molar ratio of magnesium isopropyl magnesium halide to the protected 4-iodophenylalanine of 1 to 1.5, to obtain a 4-magnesium halide of the protected phenylalanine, wherein the halide is a chloride or bromide, and the complexing base is selected from bis[2-(N,N-dimethylamino)ethyl] ether, N,N,N',N'-tetramethylethylenediamine, 1,4-diazabicyclo[2,2,2]octane, N-methylmorpholine, and N,N,N',N',N'-pentamethyldiethylenetriamine. In the second reaction step, the 4-magnesium halide is substituted with the boronic ester at a temperature of -70°C to 0°C and a molar ratio of the boronic ester to the 4-magnesium halide of the protected phenylalanine of 1 to 2. Subsequently, the resulting boronic ester group is hydrolyzed in an aqueous acidic medium at a temperature of 0°C to 50°C to obtain the protected 4-dihydroxyboronic phenylalanine. In the third reaction step, the protecting group is catalytically hydrogenolytically cracked by a Pd catalyst in an amount of 1% to 150% by weight, based on the protected 4-dihydroxyborylphenylalanine, at a hydrogen pressure of 0.1 MPa to 10 MPa and a temperature of 15°C to 120°C, in an aqueous alcoholic medium, in the presence of an organic or inorganic acid, and the reaction mixture is precipitated by adjusting the pH of the reaction mixture to 5 to 8 with an alkali at a temperature of 0°C to 50°C to obtain 4-dihydroxyborylphenylalanine.

3. The method according to claim 1 or 2, wherein the complexing base in the first reaction step is bis[2-(N,N-dimethylamino)ethyl] ether.

4. The method according to claim 1 or 2, wherein, The substitution reaction in the first reaction step is carried out under the following conditions: a temperature of -5°C to 5°C, in a tetrahydrofuran medium, and a molar ratio of isopropyl magnesium halide to the protected 4-iodophenylalanine of 1.

2.

5. The method according to claim 1 or 2, wherein, The borate ester used in the second reaction step is methyl ester or ethyl ester, and the reaction is carried out at a temperature of -25°C to -15°C.

6. The method according to claim 1 or 2, wherein, In the second reaction step, the ratio of the borate ester to the 4-magnesium halide of the protected phenylalanine is 1.

5.

7. The method according to claim 1 or 2, wherein, In the second reaction step, the aqueous acid medium is 3M to 5M hydrochloric acid at a temperature of 5°C to 25°C.

8. The method according to claim 1 or 2, wherein, The catalytic hydrogenolysis is carried out under the following conditions: the Pd catalyst is carbon-supported palladium, the amount of which is 1 to 10% by weight based on the protected 4-dihydroxyborylphenylalanine, the temperature is 30°C to 70°C, and the hydrogen pressure is 0.5 MPa to 2 MPa.

9. The method according to claim 1 or 2, wherein, The transfer hydrogenolysis in the third reaction step is carried out at 50°C to 70°C using 20% ​​to 50% by weight of palladium supported on silica with a Pd content of 20%, and with an added amount of 7% to 15% molar excess formic acid.

10. The method according to claim 1 or 2, wherein, The deprotection in the third reaction step is carried out under the following conditions: in a reaction medium containing 20% ​​to 50% water in aqueous ethanol, in the presence of hydrochloric acid, the amount of which is 0.5 to 3 molar equivalents of HCl based on the protected 4-dihydroxyborylphenylalanine.

11. The method according to claim 10, wherein the deprotection in the third reaction step is carried out under the following conditions: in a reaction medium containing 20 to 50 vol% water in aqueous ethanol, in the presence of hydrochloric acid, the amount of which is 1 to 2 molar equivalents of HCl based on the protected 4-dihydroxyborylphenylalanine.

12. The method according to claim 1 or 2, wherein, The precipitation in the third reaction step is carried out under the following conditions: pH 6 to 7, temperature 5°C to 15°C, and the use of NaOH or KOH.

13. The method according to claim 1 or 2, wherein, Following the second reaction step, the generated 4-dihydroxyborylphenylalanine is further purified by extraction with an ester solvent and washing with sodium bicarbonate solution and water, and, if necessary, by further purification with activated carbon to obtain purified and protected 4-dihydroxyborylphenylalanine.

14. The method according to claim 13, wherein, Following the second reaction step, the generated 4-dihydroxyborylphenylalanine is further purified by extraction with ethyl acetate and washing with sodium bicarbonate solution and water, and, if necessary, by further purification with activated carbon to obtain purified and protected 4-dihydroxyborylphenylalanine.

15. The method according to claim 1 or 2, wherein, The method uses L-configured phenylalanine and / or substances rich in it. 10 The boron compounds of the B isotope were used.

16. A protected 4-magnesium halide of phenylalanine as described in Formula 2, which serves as an intermediate in the preparation of 4-dihydroxyborylphenylalanine. Where R 1 and R 2 It is benzyl, or R 1 It is a benzyloxycarbonyl group, R 2 H is a radical; Bn is a benzyl group; X is Cl or Br.

17. A protected 4-dihydroxyborylphenylalanine as shown in Formula 3, which serves as an intermediate in the preparation of 4-dihydroxyborylphenylalanine. Where R 1 and R 2 It is benzyl, or R 1 It is a benzyloxycarbonyl group, R 2 H; Bn is benzyl; R 3 It is a C1 to C10 alkyl, phenyl, or benzyl group.

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