Production method of 4-10B-boric acid-L-phenylalanine with high boron atom utilization rate

Abstract

The invention provides a production method of 4-10B-boric acid-L-phenylalanine with high boron atom utilization rate, which comprises the following steps: A, adding strong base and a Turbo Grignard reagent into a 4-halogenated-phenylalanine derivative for reaction, and then adding glycol ester borane for continuous reaction to obtain a 4-boryl-phenylalanine derivative; and B, carrying out acidic hydrolysis on the 4-boryl-phenylalanine derivative, so as to obtain the 4-10B-boric acid-L-phenylalanine. The boron element is introduced into phenylalanine molecules through halogen-metal exchange and electrophilic substitution reaction, wherein the reagent combination of the Turbo Grignard reagent and the glycol ester borane ensures the efficient proceeding of the boronylation process. The production method disclosed by the invention is mild in reaction condition and simple to operate, has high-level comprehensive yield and 10B boron atom utilization rate, and provides a new way for realizing low-cost commercial production of 10B-BPA.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis and medicinal chemistry, and particularly to a 4- 10 The production method of B-boric acid-L-phenylalanine, in particular, relates to a 4- 10 Production method of B-boric acid-L-phenylalanine. Background Art

[0002] 10 B-4-boronic acid-L-phenylalanine ( 10 B-BPA) is the most widely used boron carrier in Boron Neutron Capture Therapy (BNCT) and has the best clinical therapeutic effect. It is the only two drugs approved by the US Food and Drug Administration for BNCT treatment. It is produced by Stella, Japan. 10 B-BPA has been successfully launched in 2020 and has become an effective therapeutic entity in Japan. However, as a low-toxic but less targeted BNCT boron carrier, 10 The single treatment dosage of B-BPA is high (average 20-25 grams per person), which leads to high cost of single treatment and mainly focuses on the cost of medication. 10 The cost of B-BPA has become a key factor in further promoting BNCT therapy. 10 The high synthesis cost of B-BPA is mainly due to its high abundance. 10 The high price of B raw materials and the high abundance of available 10 The price of B-boric acid is more than 10,000 times that of naturally abundant boric acid, which leads to 10 High abundance in B-BPA synthesis process 10 B raw material cost becomes the dominant factor in process cost control. Therefore, the development of high 10 New technologies for improving B atom utilization are the most effective way to reduce the cost of BNCT treatment.

[0003] However, the main technical routes for production have been realized 10 The utilization rate of B atoms is low, which provides us with a new type of high 10 The B atom utilization route leaves enough room for innovation. The earliest production method mainly used transition metal catalyzed coupling method to introduce 10 B atoms (such as US6031127A, KR20180060319A), achieve higher reaction catalytic efficiency 10However, the special raw material requirements and high catalyst dosage of the reaction have made this type of reaction unable to adapt to industrial needs and gradually eliminated. Recently in 2023, Japan's Morita Pharmaceutical Industry Co., Ltd. announced its latest design scheme (JP2023033957A), which uses cheap and practical boron protection to increase the coupling yield to near quantitative. However, 10 The B atom utilization rate is still low, only 32.0%, and the production cost is still not effectively controlled.

[0004]

[0005] The halogen-containing precursor is reacted with an alkyl metal reagent (such as alkyl lithium, Grignard reagent, etc.) to exchange metal-halogen, and then 10 B electrophilic receptor undergoes substitution reaction, thereby introducing 10 The purpose of B atom, the above electrophilic substitution scheme has become the current mainstream 10 B-BPA production strategy. Among them, metal reagents and 10 The choice of B receptor has a crucial impact on the exchange rate, intermediate stability and electrophilic substitution efficiency. Through the combination of different reagents and condition control, some companies have achieved relatively satisfactory yield control. However, 10 The B atom utilization rate, an important cost control indicator, is still low. As early as 2013, Taiwan's Xindong Biotechnology Co., Ltd. began to use this strategy to 10 Commercial production of B-BPA (US2013331599A), they use n-butyl lithium and 10 The combination of B-tributyl borate and the 10 B atom utilization.

[0006]

[0007] Subsequently, Nanjing Zhongbo Liankang Medical Technology Co., Ltd. also began to participate 10 In the production of B-BPA (US2018155368A), they used cheaper tert-butyl magnesium chloride as a metal exchange reagent and achieved a good yield improvement. However, 10 The utilization rate of B atoms has not been effectively improved.

[0008]

[0009] As the only currently available 10B-BPA comes from Japan's Stella Company. In its published production patent, it uses a Turbo Grignard reagent as a metal exchange reagent (CN116113636A). With the addition of lithium chloride, the stability of the reaction intermediate is effectively improved, which further increases the yield of the reaction. At the same time, Stella Company clearly proposed for the first time to control the 10 However, the initial attempts did not yield good results. 10 A small improvement in B atom utilization is often accompanied by a huge sacrifice in yield.

[0010]

[0011] With this as the goal, some subsequent new process developments hope to make breakthroughs in this regard. In 2023, Chongqing Gaopeng Biotechnology Co., Ltd. adopted a multi-equivalent 10 B-tributyl borate was used to improve the electrophilic substitution efficiency (CN115925732A), which achieved a certain degree of yield improvement. However, 10 The B atom utilization did not change significantly.

[0012]

[0013] In 2022, in the patent published by Chongqing Bokedi Technology Development Co., Ltd. (CN115466279A), they tried to improve the reaction efficiency by changing the order of adding materials. 10 The reaction yield was further improved by adding the B-tributyl borate solution dropwise. 10 B atom utilization is also improved.

[0014]

[0015] In addition to the above strategies of selective metal exchange reagents, other solutions are being explored. In 2019, Japan's Otsuka Pharmaceutical used a complete protection strategy to circumvent the negative effects of carboxyl anions and amino anions in the reaction (WO2019163738A), and achieved relatively good yields and moderate 10 However, the complex protection and deprotection process still affects the overall yield and 10 The B atom utilization rate caused some of the decrease.

[0016]

[0017] In 2021, in the patent published by Sichuan Yaotian Nanotechnology Co., Ltd. (CN112574245A), they replaced the commonly used iodine raw materials with brominated precursors, although the yield and10 The utilization rate of B atoms has been improved to a certain extent, but the extremely high difficulty in synthesizing high-purity brominated raw materials also makes this strategy difficult to achieve large-scale production.

[0018]

[0019] In 2023, Hainan Puli Pharmaceutical is trying to 10 B electrophilic receptor was optimized in order to screen out a more efficient electrophilic receptor (CN116925112A). After a large number of screenings, they used a special boric acid pinacol isobutyl ester as an excellent electrophilic receptor, which was able to achieve a higher yield in the electrophilic substitution step. 10 The utilization rate of B atoms is still very low.

[0020]

[0021] In summary, after nearly 30 years of synthetic process development, from coupling strategy to electrophilic substitution strategy, 10 The production efficiency of B-BPA has been significantly improved, but the cost of BNCT treatment is still high. 10 New synthetic routes for B atom utilization have become a key technical proposition for lowering the threshold for BNCT treatment. Summary of the Invention

[0022] The key technical problem to be solved by the present invention is: in the practice of BNCT treatment, 10 B atom utilization rate leads to 4- 10 B-boronic acid-L-phenylalanine ( 10 The production cost of B-BPA is too high.

[0023] In order to solve this problem, the present invention provides a 4- 10 B-boronic acid-L-phenylalanine ( 10 The method for producing B-BPA) adopts Turbo Grignard reagent as metallizing reagent and diol ester borane as electrophilic acceptor, and simultaneously achieves high reaction conversion rate and 10 B atom utilization.

[0024] The purpose of the present invention is achieved through the following technical solutions:

[0025] The present invention provides a 4- 10 The production method of B-boric acid-L-phenylalanine comprises the following steps:

[0026] A. Add a strong base and a Turbo Grignard reagent to a 4-halogenated phenylalanine derivative to react, then add a diol ester borane to continue the reaction to obtain a 4-boryl-phenylalanine derivative;

[0027] B. Acid hydrolysis of 4-boryl-phenylalanine derivatives to obtain 4- 10 B-Borate-L-Phenylalanine.

[0028] As a preferred embodiment, in step A, the 4-halogeno-phenylalanine derivative has a structure shown in the following formula (I):

[0029] Among them, R 1 is halogen; R 2 is an amino protecting group, specifically selected from tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, acetyl, trifluoroacetyl, benzoyl, benzyl, 4-methoxybenzyl; PG is a protected H atom form and a protected acetal form, and the acetal form is selected from carbon acetal, silicon acetal and boron complex.

[0030] As a preferred solution, the R 1 is any one of chlorine (Cl), bromine (Br), and iodine (I); the R 2 It is any one of tert-butyloxycarbonyl, trimethylsilylethoxycarbonyl and benzyloxycarbonyl.

[0031] As a further preferred embodiment, the 4-halogeno-phenylalanine derivative has a structure shown in the following formula (I'):

[0032] wherein R 1 is any one of chlorine (Cl), bromine (Br), and iodine (I), and more preferably R 1 is iodine (I); said R 2 It is any one of tert-butyloxycarbonyl, trimethylsilylethoxycarbonyl and benzyloxycarbonyl.

[0033] As a preferred embodiment, in step A, the strong base is selected from at least one of a first strong base and a second strong base.

[0034] As a further preferred embodiment, the first strong base comprises at least one of sodium hydride, sodium hydroxide, sodium carbonate, sodium amide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium hydride, potassium hydroxide, potassium carbonate, potassium amide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, lithium hydride, lithium hydroxide, lithium carbonate, lithium amide, lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, calcium hydride, calcium hydroxide, calcium carbonate, calcium amide, calcium methoxide, calcium ethoxide, calcium isopropoxide, calcium tert-butoxide, magnesium hydride, magnesium hydroxide, magnesium carbonate, magnesium amide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, and magnesium tert-butoxide;

[0035] The second strong base includes at least one of isopropyl lithium, butyl lithium, hexyl lithium, bis(trimethylsilyl)amide lithium, phenyl lithium, 2,2,6,6-tetramethylpiperidinium lithium, isopropyl sodium, butyl sodium, hexyl sodium, bis(trimethylsilyl)amide sodium, phenyl sodium, 2,2,6,6-tetramethylpiperidinium sodium, isopropyl potassium, butyl potassium, hexyl potassium, bis(trimethylsilyl)amide potassium, phenyl potassium, 2,2,6,6-tetramethylpiperidinium potassium, isopropyl calcium, butyl calcium, hexyl calcium, bis(trimethylsilyl)amide calcium, phenyl calcium, 2,2,6,6-tetramethylpiperidinium calcium, isopropyl magnesium, butyl magnesium, hexyl magnesium, bis(trimethylsilyl)amide magnesium, phenyl magnesium, and 2,2,6,6-tetramethylpiperidinium magnesium.

[0036] As a further preferred embodiment, the strong base is selected from at least one of sodium hydride, butyl lithium, isopropyl lithium, lithium bis(trimethylsilyl)amide, and lithium 2,6,6-tetramethylpiperidinium. More preferably, the strong base is any one of sodium hydride and n-butyl lithium; or the strong base is a combination of a first strong base and a second strong base, wherein the first strong base is sodium hydride and the second strong base is at least one of n-butyl lithium, isopropyl lithium, lithium bis(trimethylsilyl)amide, and lithium 2,6,6-tetramethylpiperidinium, and the molar ratio of the first strong base to the second strong base is 1:1 equivalents.

[0037] As a preferred embodiment, in step A, the Turbo Grignard reagent refers to a Grignard reagent with lithium chloride (LiCl) as a stabilizing agent, and its general chemical formula is R n MgX m n(LiCl), where R represents an alkyl group with 1 to 10 carbon atoms; n is in the range of 1 to 2; X represents a halogen anion (Cl, Br, I) or an alkoxy anion (RO -); the value of m is 2-n. The Turbo Grignard reagent is at least one selected from i-PrMgCl·LiCl, s-BuMgCl·LiCl, c-HexMgCl·LiCl, (s-Bu)2Mg·2(LiCl), (n-Bu)2MgCl·2LiCl, s-BuMg(Ot-Bu)·LiCl, and s-BuMg(OMe)·LiCl. More preferably, the Turbo Grignard reagent is i-PrMgCl·LiCl, (s-Bu)2MgCl·2LiCl, (n-Bu)2MgCl·2LiCl, s-BuMg(Ot-Bu)·LiCl, and s-BuMg(OMe)·LiCl. The most preferred Turbo Grignard reagent is i-PrMgCl·LiCl or (s-Bu)2MgCl·2LiCl.

[0038] As a preferred embodiment, in step A, the diol ester borane refers to a dialkoxy-substituted monohydroborane compound having any of the following structures of formula (IV) to formula (XIII), wherein the boron atom is represented by 11 B or 10 B:

[0039]

[0040] As a preferred embodiment, the diol ester borane has a structure of any one of formula (IV) to formula (VII), formula (IX), and formula (X).

[0041] As a preferred embodiment, in step A, the molar ratio of the 4-halogeno-phenylalanine derivative and the strong base is 1.0:0.0-5.0 equivalents, and more preferably the molar ratio of the 4-halogeno-phenylalanine derivative and the strong base is 1.0:1.0-2.0 equivalents.

[0042] The molar ratio of the 4-halogeno-phenylalanine derivative to the Turbo Grignard reagent is 1.0:1.0-10.0 equivalents, and more preferably the molar ratio of the 4-halogeno-phenylalanine derivative to the Turbo Grignard reagent is 1.0:1.0-2.0 equivalents.

[0043] The molar ratio of the 4-halogeno-phenylalanine derivative and the diol ester borane is 1.0:1.0 to 10.0 equivalents, more preferably the molar ratio of the 4-halogeno-phenylalanine derivative and the diol ester borane is 1.0:1.0 to 2.0 equivalents, and most preferably the molar ratio of the 4-halogeno-phenylalanine derivative and the diol ester borane is 1.0:1.0 to 1.1 equivalents.

[0044] As a preferred embodiment, in step B, hydrochloric acid is added during the acidic hydrolysis; the molar ratio of the 4-halogenated-phenylalanine derivative to hydrochloric acid is 1.0:3.0-100.0 equivalents.

[0045] Compared with the prior art, the present invention has the following beneficial effects:

[0046] 1. The present invention uses 4-halogenated phenylalanine derivatives as starting materials, selects Turbo Grignard reagent as metal exchange reagent and diol ester borane as electrophilic acceptor to complete the borylation reaction at position 4 of phenylalanine derivatives. The overall process has mild conditions, simple operation, and stable material properties in each step, which can meet the needs of large-scale production.

[0047] 2. In the present invention, Turbo Grignard reagent is selected as the metal exchange reagent for 4-halogeno-phenylalanine derivatives, which has the characteristics of fast exchange speed. In addition, since the formed aryl metal intermediate is stable in nature, the exchange process does not require ultra-low temperature control, thereby ensuring the efficient progress of the subsequent borylation reaction.

[0048] 3. The present invention selects diol ester borane as the electrophilic acceptor, which has two advantages: first, the ability of diol ester borane to accept electrophilic attack is higher than that of boric acid triester compounds, which makes the reaction more thorough and helps to improve the reaction efficiency. 10 B atom utilization rate; secondly, after receiving electrophilic attack, diol ester boranes will exist in the form of stable tetravalent borate intermediates, which can avoid impurities and losses caused by excessive reaction compared with boric acid triester compounds.

[0049] 4. Each step of the reaction in the present invention has a high reaction efficiency, and the comprehensive yield of the two steps is 10 The utilization rate of boron atoms is above 60%; and the comprehensive yield of the two steps can reach up to 85%. 10 The utilization rate of boron atoms can reach up to 75%.

[0050] 5. The conditions and applicable scope of the present invention can be expanded to the pilot scale, and the comprehensive yield and 10 B Boron atom utilization rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Other features, objects and advantages of the present invention will become more apparent upon reading the detailed description of non-limiting embodiments with reference to the following drawings:

[0052] Figure 1 4- 10 B-boric acid-L-phenylalanine 1 H NMR spectrum;

[0053] Figure 2 4- 10 HPLC spectrum of B-boronic acid-L-phenylalanine. DETAILED DESCRIPTION

[0054] The present invention will be described in detail below with reference to specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those skilled in the art, several variations and improvements can be made without departing from the scope of the present invention. These all fall within the scope of protection of the present invention.

[0055] In a specific embodiment of the present invention, a 4- 10 The production method of B-boric acid-L-phenylalanine specifically comprises the following two steps:

[0056]

[0057] Step 1: Prepare 4-boryl-phenylalanine derivatives through halogen-metal exchange and electrophilic substitution process from formula (I) to formula (II):

[0058] A 4-halogenated phenylalanine derivative (Formula I) and solvent A are added to a reactor, stirred to dissolve, and then cooled at -30 to 25°C. A strong base is added thereto, followed by a Turbo Grignard reagent, which is then added dropwise. After the addition is complete, the temperature is returned to room temperature and stirring is continued until the reaction is complete. Then, a solution of a glycol ester borane in solvent A is added dropwise to the system. After the addition is complete, stirring is continued at room temperature until the reaction is complete. After the reaction is complete, the pH of the system is adjusted to not less than 7.0, and the organic phase obtained after extraction with solvent B is dried and rotary evaporated to obtain the corresponding 4-boryl-phenylalanine derivative (Formula II).

[0059] In a specific embodiment, the ratio of the 4-halogeno-phenylalanine derivative to solvent A is 1.0 g: 0.5-20.0 mL; the molar ratio of the 4-halogeno-phenylalanine derivative to the strong base is 1.0: 0.0-5.0 equivalents; the molar concentration of the Turbo Grignard reagent is 0.5-5.0 mol / L; the molar ratio of the 4-halogeno-phenylalanine derivative to the Turbo Grignard reagent is 1.0: 1.0-10.0 equivalents; the molar concentration of the solvent A solution of the diol ester borane is 0.5-5.0 mol / L; the molar ratio of the 4-halogeno-phenylalanine derivative to the diol ester borane is 1.0: 1.0-10.0 equivalents; and the ratio of the 4-halogeno-phenylalanine derivative to solvent B is 1.0 g: 5.0-50.0 mL.

[0060] In one embodiment, the 4-halogeno-phenylalanine derivative has a structure shown in the following formula (I):

[0061] Among them, R1 is a halogen, among which I (iodine) has the best reaction effect; R 2 is an amino protecting group, specifically selected from tert-butyloxycarbonyl (Boc), methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), benzyloxycarbonyl (Cbz), acetyl (Ac), trifluoroacetyl, benzoyl (Bz), benzyl (Bn), and 4-methoxybenzyl (PMB); PG is a protected H atom form and a protected acetal form, and the acetal form is selected from carbon acetal, silicon acetal and boron complex, and different protection forms have obvious differences in reaction effects according to different reaction conditions used.

[0062] In a specific embodiment, the solvent A refers to an aprotic solvent, including at least one of an ether solvent (such as diethyl ether, propyl ether, butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, methyl cyclopentyl ether, dioxane, methyl dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether), an aromatic hydrocarbon solvent (such as benzene, toluene) and an alkane solvent (such as hexane, heptane, octane), all of which can obtain high comprehensive yield and high boron atom utilization rate; among them, ether solvents have the best reaction effect.

[0063] In one embodiment, the strong base is selected from at least one of a first strong base and a second strong base;

[0064] wherein the first strong base comprises at least one of sodium hydride (NaH), sodium hydroxide (NaOH), sodium carbonate (Na2CO3), sodium amide (NaNH2), sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium hydride, potassium hydroxide, potassium carbonate, potassium amide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, lithium hydride, lithium hydroxide, lithium carbonate, lithium amide, lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, calcium hydride, calcium hydroxide, calcium carbonate, calcium amide, calcium methoxide, calcium ethoxide, calcium isopropoxide, calcium tert-butoxide, magnesium hydride, magnesium hydroxide, magnesium carbonate, magnesium amide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, and magnesium tert-butoxide;

[0065] The second strong base includes isopropyl lithium (LDA), butyl lithium (including n-butyl lithium, sec-butyl lithium, tert-butyl lithium), hexyl lithium, lithium bis(trimethylsilyl)amide (LiHMDS), phenyl lithium, 2,2,6,6-tetramethylpiperidinium lithium (TMPLi), isopropyl sodium, butyl sodium (including n-butyl sodium, sec-butyl sodium, tert-butyl sodium), hexyl sodium, sodium bis(trimethylsilyl)amide, phenyl sodium, 2,2,6,6-tetramethylpiperidinium sodium, isopropyl potassium, butyl potassium (including n-butyl potassium, sec-butyl potassium , tert-butyl potassium), hexyl potassium, bis(trimethylsilyl)amide potassium, phenyl potassium, 2,2,6,6-tetramethylpiperidinium potassium, isopropyl calcium, butyl calcium (including n-butyl calcium, sec-butyl calcium, tert-butyl calcium), hexyl calcium, bis(trimethylsilyl)amide calcium, phenyl calcium, 2,2,6,6-tetramethylpiperidinium calcium, isopropyl magnesium, butyl magnesium (including n-butyl magnesium, sec-butyl magnesium, tert-butyl magnesium), hexyl magnesium, bis(trimethylsilyl)amide magnesium, phenyl magnesium, 2,2,6,6-tetramethylpiperidinium magnesium.

[0066] In a specific embodiment, the Turbo Grignard reagent is selected from at least one of i-PrMgCl·LiCl, s-BuMgCl·LiCl, c-HexMgCl·LiCl, (s-Bu)2Mg·2(LiCl), (n-Bu)2MgCl·2LiCl, s-BuMg(Ot-Bu)·LiCl, and s-BuMg(OMe)·LiCl.

[0067] In one embodiment, the structural formula of the diol ester borane is where R 3 Refers to a chain or cyclic hydrocarbon group with 1 to 15 carbon atoms. More specifically, the diol ester borane has any of the following structures: (IV) to (XIII), wherein the boron atom is 11 B or 10 B (all used in the following examples are 10 B):

[0068]

[0069] In a specific embodiment, the solvent B refers to at least one of the following two types of solvents: ester solvents, including ethyl formate, isobutyl formate, ethyl acetate, propyl acetate, isobutyl acetate, ethyl propionate, and isobutyl propionate; alcohol solvents, including n-butanol; among which ethyl acetate, isobutyl acetate, and n-butanol have the best extraction effects.

[0070] Step 2: Acidic hydrolysis to obtain 4- 10 B-boronic acid-L-phenylalanine ( 10 B-BPA), from formula (II) to formula (III):

[0071] 4-boryl-phenylalanine derivative (Formula (II)), solvent C and hydrochloric acid are added to the reactor, heated to 30-80°C and stirred until the raw materials are completely consumed; after the reaction is completed, the organic solvent is removed by rotary evaporation, and the aqueous layer is washed with solvent D; then, the aqueous layer is cooled to 0-25°C, the pH of the system is adjusted to about 6.0, and the mixture is allowed to stand and then filtered, and the filter cake is washed with solvent E to finally obtain pure 4-boryl-phenylalanine derivative (Formula (II)). 10 B-boronic acid-L-phenylalanine (Formula (III)).

[0072] In a specific embodiment, the ratio of the 4-boryl-phenylalanine derivative and solvent C is 1.0 g: 0.5-30.0 mL; the concentration of the hydrochloric acid is 1.0-6.0 N; and the molar ratio of the 4-halogenated-phenylalanine derivative and hydrochloric acid is 1.0: 3.0-100.0 equivalents.

[0073] In a specific embodiment, the solvent C refers to at least one of two types of solvents: ketone solvents, including acetone, methyl propyl ketone, and methyl isobutyl ketone; alcohol solvents, including methanol, ethanol, isopropanol, ethylene glycol, and propylene glycol; among which acetone, methyl isobutyl ketone, and isopropanol have the best reaction effect.

[0074] The solvent D refers to at least one of three types of solvents: ester solvents, including ethyl formate, isobutyl formate, ethyl acetate, propyl acetate, isobutyl acetate, ethyl propionate, and isobutyl propionate; ether solvents, including ethyl ether, propyl ether, butyl ether, and methyl tert-butyl ether; and alcohol solvents, including butanol and pentanol; among them, ethyl acetate, isobutyl acetate, ethyl ether, methyl tert-butyl ether, and butanol have the best washing effect.

[0075] The solvent E refers to at least one of two types of solvents: alcohol solvents, including methanol, ethanol, and isopropanol; and halogenated alkane solvents, including dichloromethane, dichloroethane, and trichloroethane; among which methanol and dichloromethane have the best purification effect.

[0076] In the present invention, the boron atom utilization rate is calculated using the following formula (the boron atom utilization rates obtained in the various literature mentioned in the background art are also calculated):

[0077] Boron atom utilization rate = (number of boron atoms in the theoretical product × actual product yield) ÷ (number of boron atoms in the boron source reagent used × equivalent amount of boron source reagent used)

[0078] Taking Example 1 as an example, the calculation of its boron atom utilization is: the number of boron atoms in the theoretical product = 1; the actual product yield = 86.1%; the number of boron atoms in the boron source reagent used = 1; the equivalent amount of the boron source reagent used = 13.4 / 12.8 = 1.05; therefore, the boron atom utilization = (1×86.1%) ÷ (1×1.05) = 82%.

[0079] In the embodiments of the present invention, the 4-halogeno-phenylalanine derivatives, diol ester boranes, etc. used can be purchased commercially or prepared by conventional methods (such as methods reported in the literature), and the raw materials are widely available.

[0080] Example 1

[0081] This embodiment provides a 4- 10 The production method of B-boric acid-L-phenylalanine, the reaction formula is as follows:

[0082]

[0083] The specific steps are as follows: 1) 4-iodo-N-Boc-phenylalanine (5.0 g, 12.8 mmol) and THF (10 mL) were added to a dry reactor A, stirred and dissolved, and then cooled at -30°C. Sodium hydride powder (0.5 g, 12.8 mmol, 60 wt%) was added to the system. After no more bubbles were emitted, n-butyl lithium solution (5.3 mL, 12.8 mmol, 2.4 M n-hexane solution) was added dropwise to the system. The system was controlled to The temperature was not higher than 25° C., and i-PrMgCl·LiCl solution (25.5 mL, 25.5 mmol, 1.0 M THF solution) was added dropwise to the system and the system temperature was kept below 25° C. After stirring for 5 hours, the metal exchange process was confirmed to be complete by HPLC. Then, a THF solution of 4,4,5,5-tetraethyl-1,3,2-dioxaborolane (Formula IV) (2.47 g, 13.4 mmol, dissolved in 10 mL THF) was added dropwise to the system. After the addition was complete, the system was gradually restored to room temperature and stirred for 5 hours. The borylation reaction was confirmed to be complete by HPLC. After the reaction was complete, 1N dilute hydrochloric acid was added dropwise to the system and the pH of the system was adjusted to about 7.0. The aqueous layer was extracted three times with isobutyl acetate (10 mL) and the organic phases were combined. The organic phases were dried and rotary evaporated to obtain the corresponding 4- 10 The crude B-boryl-N-Boc-phenylalanine was directly carried into the next step without purification.

[0084] 2) Add the 4- 10Crude B-boryl-N-Boc-phenylalanine, acetone (20 mL) and hydrochloric acid (7.5 g, 76.7 mmol, 37 wt%) were heated to 60° C. and then stirred and refluxed for 2 hours. HPLC monitoring confirmed that the raw materials were completely consumed. After the reaction was completed, acetone was removed as much as possible by rotary evaporation, and the aqueous phase was washed three times with isobutyl acetate (10 mL) and the aqueous phase was retained. Then, the beaker containing the aqueous phase was placed in an ice-water bath, and 3N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to about 6.0. After standing for 2 hours, it was filtered, and the filter cake was washed with a small amount of methanol. The filter cake was slurried with dichloromethane (10 mL) to finally obtain pure 4- 10 B-boronic acid-L-phenylalanine 2.30g, the comprehensive yield reached 86.1%, and the boron atom utilization rate reached 82%. 10 B-boric acid-L-phenylalanine 1 H NMR spectrum Figure 1 As shown, the HPLC spectrum is as Figure 2 shown.

[0085] The method of this embodiment is used to replace the sodium hydride powder used in step 1) with other strong bases of equal amount, and the obtained 4- 10 The comprehensive yield of B-boronic acid-L-phenylalanine and the utilization rate of boron atoms are shown in Table 1 below.

[0086] Table 1 Results of reactions using different strong bases

[0087]

[0088]

[0089] As can be seen from the results in Table 1, when the strong base is sodium hydride, the obtained 4- 10 The comprehensive yield and boron atom utilization rate of B-boronic acid-L-phenylalanine were the highest, both reaching more than 80%; followed by n-butyl lithium, isopropyl lithium, bis(trimethylsilyl)amide lithium and 2,2,6,6-tetramethylpiperidinium lithium. 10 The comprehensive yield of B-boronic acid-L-phenylalanine and the utilization rate of boron atoms are both above 70%. 10 The comprehensive yield and boron atom utilization rate of B-boronic acid-L-phenylalanine are both less than 15%.

[0090] Example 2

[0091] This embodiment provides a 4- 10 The production method of B-boric acid-L-phenylalanine, the reaction formula is as follows:

[0092]

[0093] The specific steps are as follows: 1) adding 4-iodo-N-Boc-phenylalanine (5.0 g, 12.8 mmol) and THF (10 mL) to a dry reactor A, stirring and dissolving, and then cooling at -30°C, adding n-butyllithium solution (10.6 mL, 25.6 mmol, 2.4 M n-hexane solution) dropwise to the system, controlling the system temperature not to exceed 25°C, then adding (s-Bu)2MgCl·2LiCl (12.8 mL, 12.2 mmol, 0.8 M THF solution) dropwise to the system, maintaining the system temperature not to exceed 25°C, continuing stirring for 5 hours, and confirming the completion of the metal exchange process by HPLC detection; then, adding 4,4,5,5-tetraethyl-1,3,2-dioxaborolane (Formula V) THF solution (2.47 g, 13.4 mmol, dissolved in 10 mL) dropwise to the system. After the addition was complete, the system was gradually restored to room temperature and stirred for 5 hours. HPLC detection confirmed that the borylation reaction was complete. After the reaction was completed, 1N dilute hydrochloric acid was added dropwise to the system and the pH of the system was adjusted to about 7.0. The aqueous layer was extracted three times with isobutyl acetate (10 mL) and the organic phase was combined. The organic phase was dried and rotary evaporated to obtain the corresponding 4- 10 The crude B-boryl-N-Boc-phenylalanine was directly carried into the next step without purification.

[0094] 2) Add the 4- 10 Crude B-boryl-N-Boc-phenylalanine, acetone (20 mL) and hydrochloric acid (7.5 g, 76.7 mmol, 37 wt%) were heated to 60° C. and then stirred and refluxed for 2 hours. HPLC monitoring confirmed that the raw materials were completely consumed. After the reaction was completed, acetone was removed as much as possible by rotary evaporation, and the aqueous phase was washed three times with isobutyl acetate (10 mL) and the aqueous phase was retained. Then, the beaker containing the aqueous phase was placed in an ice-water bath, and 3N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to about 6.0. After standing for 2 hours, it was filtered, and the filter cake was washed with a small amount of methanol. The filter cake was slurried with dichloromethane (10 mL) to finally obtain pure 4- 10 2.26 g of B-boric acid-L-phenylalanine was obtained, with a comprehensive yield of 84.6% and a boron atom utilization rate of 80%.

[0095] By using the method of this embodiment, only the (s-Bu)2MgCl·2LiCl used in step 1) is replaced by other Turbo Grignard reagents or other non-Turbo Grignard reagents, and the obtained 4- 10 The comprehensive yield of B-boronic acid-L-phenylalanine and the utilization rate of boron atoms are shown in Table 2 below.

[0096] Table 2 Results of reactions using different Turbo Grignard reagents

[0097]

[0098]

[0099] From the results in Table 2, it can be seen that the 4- 10 The comprehensive yield of B-boronic acid-L-phenylalanine and the utilization rate of boron atoms are both above 65%. When the Turbo Grignard reagent is i-PrMgCl·LiCl or (s-Bu)2MgCl·2LiCl, the obtained 4- 10 The comprehensive yield and boron atom utilization rate of B-boronic acid-L-phenylalanine were the highest, both reaching more than 80%; followed by (n-Bu)2MgCl·2LiCl, s-BuMg(Ot-Bu)·LiCl, and s-BuMg(OMe)·LiCl. 10 The comprehensive yield and boron atom utilization rate of B-boronic acid-L-phenylalanine both reached over 70%. 10 The comprehensive yield and boron atom utilization rate of B-boric acid-L-phenylalanine are both below 50%, and the effect is poor.

[0100] Example 3

[0101] This embodiment provides a 4- 10 The production method of B-boric acid-L-phenylalanine, the reaction formula is as follows:

[0102]

[0103] The specific steps are as follows: 1) adding 4-iodo-N-Boc-phenylalanine (5.0 g, 12.8 mmol) and THF (10 mL) to a dry reactor A, stirring and dissolving, and then cooling at -30°C, adding n-butyllithium solution (10.6 mL, 25.6 mmol, 2.4 M n-hexane solution) dropwise to the system, controlling the system temperature not to exceed 25°C, then adding i-PrMgCl·LiCl solution (25.5 mL, 25.5 mmol, 1.0 M THF solution) dropwise to the system, maintaining the system temperature not to exceed 25°C, continuing stirring for 5 hours, and then confirming the completion of the metal exchange process by HPLC detection; then, adding 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Formula IV) THF solution (1.80 g, 14.1 mmol, dissolved in 10 mL After the addition was complete, the system was gradually restored to room temperature and stirred for 5 hours. HPLC detection confirmed that the borylation reaction was complete. After the reaction was completed, 1N dilute hydrochloric acid was added dropwise to the system and the pH of the system was adjusted to about 7.0. The aqueous layer was extracted three times with isobutyl acetate (10 mL) and the organic phase was combined. The organic phase was dried and rotary evaporated to obtain the corresponding 4- 10 The crude B-boryl-N-Boc-phenylalanine was directly carried into the next step without purification.

[0104] 2) Add the 4- 10 Crude B-boryl-N-Boc-phenylalanine, acetone (20 mL) and hydrochloric acid (7.5 g, 76.7 mmol, 37 wt%) were heated to 60° C. and then stirred and refluxed for 2 hours. HPLC monitoring confirmed that the raw materials were completely consumed. After the reaction was completed, acetone was removed as much as possible by rotary evaporation, and the aqueous phase was washed three times with isobutyl acetate (10 mL) and the aqueous phase was retained. Then, the beaker containing the aqueous phase was placed in an ice-water bath, and 3N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to about 6.0. After standing for 2 hours, it was filtered, and the filter cake was washed with a small amount of methanol. The filter cake was slurried with dichloromethane (10 mL) to finally obtain pure 4- 10 2.23 g of B-boric acid-L-phenylalanine was obtained, with a comprehensive yield of 83.5% and a boron atom utilization rate of 75%.

[0105] The method of this embodiment is used to replace the 4,4,5,5-tetramethyl-1,3,2-dioxaborane used in step 1) with other diol ester boranes to obtain 4- 10 The comprehensive yield of B-boronic acid-L-phenylalanine and the utilization rate of boron atoms are shown in Table 3 below.

[0106] Table 3 Results of reactions using different diol ester boranes

[0107]

[0108]

[0109] From the results in Table 3, it can be seen that when the diol ester borane used is a compound represented by Formula V or Formula X, the obtained 4- 10 The comprehensive yield and boron atom utilization rate of B-boronic acid-L-phenylalanine were the highest, both reaching more than 80%; followed by the compounds represented by formula IV and formula VI, and the obtained 4- 10 The comprehensive yield of B-boronic acid-L-phenylalanine reaches more than 80%, and the boron atom utilization rate reaches more than 75%; the next is the compound represented by formula VII and formula IX, and the obtained 4- 10 The comprehensive yield and boron atom utilization rate of B-boronic acid-L-phenylalanine are both above 60%. When the diol ester borane used is a compound represented by Formula VIII, Formula XI, Formula XII, or Formula XIII, the obtained 4- 10 The comprehensive yield and boron atom utilization of B-boronic acid-L-phenylalanine were both 60% lower.

[0110] Example 4

[0111] This embodiment provides a 4- 10 The production method of B-boric acid-L-phenylalanine, the reaction formula is as follows:

[0112]

[0113] The specific steps are as follows: 1) adding 4-iodo-N-Boc-phenylalanine (5.0 g, 12.8 mmol) and THF (10 mL) to a dry reactor A, stirring to dissolve, and then cooling at -30°C, adding sodium hydride powder (0.5 g, 12.8 mmol, 60 wt%) to the system, waiting until no more bubbles emerge, adding n-butyl lithium solution (5.3 mL, 12.8 mmol, 2.4 M n-hexane solution) to the system dropwise, controlling the system temperature not to exceed 25°C, then adding i-PrMgCl·LiCl solution (25.5 mL, 25.5 mmol, 1.0 M THF solution) to the system dropwise, maintaining the system temperature not to exceed 25°C, and continuing stirring for 5 hours. After that, the metal exchange process is confirmed to be complete by HPLC detection; then, adding 4,4,5,5-tetraethyl-1,3,2-dioxa- 10 After the addition of a THF solution of B-borane (2.47 g, 13.4 mmol, dissolved in 10 mL of THF), the system was gradually restored to room temperature and stirred for 5 hours. HPLC detection confirmed that the borylation reaction was complete. After the reaction was completed, 1N dilute hydrochloric acid was added dropwise to the system and the pH of the system was adjusted to about 7.0. The aqueous layer was extracted three times with isobutyl acetate (10 mL) and the organic phases were combined. The organic phases were dried and rotary evaporated to obtain the corresponding 4-10 The crude B-boryl-N-Boc-phenylalanine was directly carried into the next step without purification.

[0114] Add the 4- 10 Crude B-boryl-N-Boc-phenylalanine, acetone (20 mL) and hydrochloric acid (7.5 g, 76.7 mmol, 37 wt%) were heated to 60° C. and then stirred and refluxed for 2 hours. HPLC monitoring confirmed that the raw materials were completely consumed. After the reaction was completed, acetone was removed as much as possible by rotary evaporation, and the aqueous phase was washed three times with isobutyl acetate (10 mL) and the aqueous phase was retained. Then, the beaker containing the aqueous phase was placed in an ice-water bath, and 3N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to about 6.0. After standing for 2 hours, it was filtered, and the filter cake was washed with a small amount of methanol. The filter cake was slurried with dichloromethane (10 mL) to finally obtain pure 4- 10 B-boric acid-L-phenylalanine 2.28g, the overall yield reached 85.7%, 10 The B atom utilization rate reaches 82%.

[0115] Example 5

[0116] This embodiment provides a 4- 10 The production method of B-boric acid-L-phenylalanine, the reaction formula is as follows:

[0117]

[0118] The specific steps are as follows: 1) adding 4-bromo-N-Boc-phenylalanine (4.4 g, 12.8 mmol) and THF (10 mL) to a dry reactor A, stirring and dissolving, and then cooling at -30°C, adding n-butyl lithium solution (10.6 mL, 25.6 mmol, 2.4 M n-hexane solution) dropwise to the system, controlling the system temperature not to exceed 25°C, then adding i-PrMgCl·LiCl solution (25.5 mL, 25.5 mmol, 1.0 M THF solution) dropwise to the system, maintaining the system temperature not to exceed 25°C, continuing stirring for 5 hours, and confirming the completion of the metal exchange process by HPLC detection; then, adding 4,4,5,5-tetraethyl-1,3,2-dioxaborolane THF solution (2.47 g, 13.4 mmol, dissolved in 10 mL After the addition was complete, the system was gradually restored to room temperature and stirred for 5 hours. HPLC detection confirmed that the borylation reaction was complete. After the reaction was completed, 1N dilute hydrochloric acid was added dropwise to the system and the pH of the system was adjusted to about 7.0. The aqueous layer was extracted three times with isobutyl acetate (10 mL) and the organic phase was combined. The organic phase was dried and rotary evaporated to obtain the corresponding 4- 10 The crude B-boryl-N-Boc-phenylalanine was directly carried into the next step without purification.

[0119] 2) Add the 4- 10 Crude B-boryl-N-Boc-phenylalanine, acetone (20 mL) and hydrochloric acid (7.5 g, 76.7 mmol, 37 wt%) were heated to 60° C. and then stirred and refluxed for 2 hours. HPLC monitoring confirmed that the raw materials were completely consumed. After the reaction was completed, acetone was removed as much as possible by rotary evaporation, and the aqueous phase was washed three times with isobutyl acetate (10 mL) and the aqueous phase was retained. Then, the beaker containing the aqueous phase was placed in an ice-water bath, and 3N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to about 6.0. After standing for 2 hours, it was filtered, and the filter cake was washed with a small amount of methanol. The filter cake was slurried with dichloromethane (10 mL) to finally obtain pure 4- 10 1.8 g of B-boric acid-L-phenylalanine was obtained, with a comprehensive yield of 67.4% and a boron atom utilization rate of 64%.

[0120] Example 6

[0121] This embodiment provides a 4- 10 The production method of B-boric acid-L-phenylalanine, the reaction formula is as follows:

[0122]

[0123] The specific steps are as follows: 1) adding 4-iodo-N-Boc-phenylalanine tert-butyl ester (5.7 g, 12.8 mmol) and THF (10 mL) to a dry reactor A, stirring and dissolving, and then cooling at -30°C, adding n-butyl lithium solution (5.3 mL, 12.8 mmol, 2.4 M n-hexane solution) dropwise to the system, controlling the system temperature not to exceed 25°C, then adding i-PrMgCl·LiCl solution (25.5 mL, 25.5 mmol, 1.0 M THF solution) dropwise to the system, maintaining the system temperature not to exceed 25°C, and continuing stirring for 5 hours after which the metal exchange process is confirmed to be complete by HPLC detection; then, adding 4,4,5,5-tetraethyl-1,3,2-dioxaborolane THF solution (2.58 g, 14.0 mmol, dissolved in 10 mL) dropwise to the system; After the addition was complete, the system was gradually restored to room temperature and stirred for 5 hours. HPLC detection confirmed that the borylation reaction was complete. After the reaction was completed, 1N dilute hydrochloric acid was added dropwise to the system and the pH of the system was adjusted to about 7.0. The aqueous layer was extracted three times with isobutyl acetate (10 mL) and the organic phase was combined. The organic phase was dried and rotary evaporated to obtain the corresponding 4- 10 The crude product of B-boryl-N-Boc-phenylalanine tert-butyl ester was directly used for the next step without purification.

[0124] 2) Add the 4- 10The crude product of B-boryl-N-Boc-phenylalanine tert-butyl ester, acetone (20 mL) and hydrochloric acid (7.5 g, 76.7 mmol, 37 wt%) were heated to 60° C. and then stirred and refluxed for 6 hours. The complete consumption of the starting materials was confirmed by HPLC monitoring. After the reaction was completed, acetone was removed as much as possible by rotary evaporation, and the aqueous phase was washed three times with isobutyl acetate (10 mL) and the aqueous phase was retained. Then, the beaker containing the aqueous phase was placed in an ice-water bath, and 3N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to about 6.0. After standing for 2 hours, it was filtered, and the filter cake was washed with a small amount of methanol. The filter cake was slurried with dichloromethane (10 mL) to finally obtain pure 4- 10 2.43 g of B-boronic acid-L-phenylalanine was obtained, with a comprehensive yield of 91.0% and a boron atom utilization rate of 83%. The 4-iodo-N-Boc-phenylalanine tert-butyl ester used in this example can be prepared by conventional methods. In the actual production process, 4-iodo-N-Boc-phenylalanine is still used as the raw material to better meet the cost priority principle.

[0125] Example 7

[0126] This embodiment provides a 4- 10 The production method of B-boric acid-L-phenylalanine, the reaction formula is as follows:

[0127]

[0128] The specific steps are as follows: 1) adding 4-iodo-N-Boc-phenylalanine (5.0 g, 12.8 mmol) and THF (10 mL) to a dry reactor A, stirring and dissolving, and then cooling at -30°C, adding n-butyllithium solution (5.3 mL, 12.8 mmol, 2.4 M n-hexane solution) dropwise to the system, controlling the system temperature not to exceed 25°C, then adding i-PrMgCl·LiCl solution (25.5 mL, 25.5 mmol, 1.0 M THF solution) dropwise to the system, maintaining the system temperature not to exceed 25°C, continuing stirring for 5 hours, and then confirming the completion of the metal exchange process by HPLC detection; then, adding 4,4,5,5-tetraethyl-1,3,2-dioxaborolane (Formula V) THF solution (2.47 g, 13.4 mmol, dissolved in 10 mL After the addition was complete, the system was gradually restored to room temperature and stirred for 5 hours. HPLC detection confirmed that the borylation reaction was complete. After the reaction was completed, 1N dilute hydrochloric acid was added dropwise to the system and the pH of the system was adjusted to about 7.0. The aqueous layer was extracted three times with n-butanol (10 mL) and the organic phase was combined. The organic phase was dried and rotary evaporated to obtain the corresponding 4- 10 The crude B-boryl-N-Boc-phenylalanine was directly carried into the next step without purification.

[0129] 2) Add the 4- 10 Crude B-boryl-N-Boc-phenylalanine, acetone (20 mL) and hydrochloric acid (7.5 g, 76.7 mmol, 37 wt%) were heated to 60° C. and then stirred and refluxed for 6 hours. HPLC monitoring confirmed that the raw materials were completely consumed. After the reaction was completed, acetone was removed as much as possible by rotary evaporation, and the aqueous phase was washed three times with n-butanol (10 mL) and the aqueous phase was retained. Then, the beaker containing the aqueous phase was placed in an ice-water bath, and 3N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to about 6.0. After standing for 2 hours, it was filtered, and the filter cake was washed with a small amount of methanol. The filter cake was slurried with dichloromethane (10 mL) to finally obtain pure 4- 10 2.15 g of B-boric acid-L-phenylalanine was obtained, with a comprehensive yield of 80.5% and a boron atom utilization rate of 77%.

[0130] Example 8

[0131] This embodiment provides a 4- 10 The production method of B-boric acid-L-phenylalanine, the reaction formula is as follows:

[0132]

[0133] The specific steps are as follows: 1) adding 4-iodo-N-Boc-phenylalanine (30.0 g, 76.7 mmol) and THF (50 mL) to a dry reactor A, stirring and dissolving, and then cooling at -30°C. Then, adding sodium hydride powder (3.1 g, 76.7 mmol, 60 wt%) to the system, and after no more bubbles emerge, adding n-butyl lithium solution (31.9 mL, 76.7 mmol, 2.4 M n-hexane solution) dropwise to the system, controlling the system temperature not to exceed 25°C, and then adding i-PrMgCl·LiCl solution (99.7 mL, 99.7 mmol, 1.0 M THF solution) dropwise to the system while maintaining the system temperature not to exceed 25°C. After continuing stirring for 6 hours, the metal exchange process is confirmed to be complete by HPLC detection; then, adding 4,4,5,5-tetraethyl-1,3,2-dioxaborolane THF solution (14.8 g, 80.5 mmol, dissolved in 30 mL After the addition was complete, the system was gradually restored to room temperature and stirred for 10 hours. HPLC detection confirmed that the borylation reaction was complete. After the reaction was completed, 1N dilute hydrochloric acid was added dropwise to the system and the pH of the system was adjusted to about 7.0. The aqueous layer was extracted three times with isobutyl acetate (40 mL) and the organic phases were combined. The organic phases were dried and rotary evaporated to obtain the corresponding 4- 10 The crude B-boryl-N-Boc-phenylalanine was directly carried into the next step without purification.

[0134] 2) Add the 4-10 Crude B-boryl-N-Boc-phenylalanine, acetone (50 mL) and hydrochloric acid (45.0 g, 460.0 mmol, 37 wt%) were heated to 60° C. and then stirred and refluxed for 5 hours. HPLC monitoring confirmed that the raw materials were completely consumed. After the reaction was completed, acetone was removed as much as possible by rotary evaporation, and the aqueous phase was washed three times with isobutyl acetate (25 mL) and the aqueous phase was retained. Then, the beaker containing the aqueous phase was placed in an ice-water bath, and 3N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to about 6.0. After standing for 4 hours, it was filtered, and the filter cake was washed with methanol. The filter cake was slurried with dichloromethane (40 mL) to finally obtain pure 4- 10 13.2 g of B-boric acid-L-phenylalanine was obtained, with a comprehensive yield of 82.4% and a boron atom utilization rate of 79%.

[0135] Example 9

[0136] This embodiment provides a 4- 10 The production method of B-boric acid-L-phenylalanine, the reaction formula is as follows:

[0137]

[0138] The specific steps are as follows: 1) adding 4-iodo-N-acetyl-phenylalanine (4.3 g, 12.8 mmol) and THF (10 mL) to a dry reactor A, stirring and dissolving, and then cooling at -30°C, adding n-butyl lithium solution (10.6 mL, 25.6 mmol, 2.4 M n-hexane solution) dropwise to the system, controlling the system temperature not to exceed 25°C, then adding i-PrMgCl·LiCl solution (25.5 mL, 25.5 mmol, 1.0 M THF solution) dropwise to the system and maintaining the system temperature not to exceed 25°C, continuing stirring for 5 hours, and then confirming the completion of the metal exchange process by HPLC detection; then, adding 4,4,5,5-tetraethyl-1,3,2-dioxaborolane THF solution (2.47 g, 13.4 mmol, dissolved in 10 mL) dropwise to the system; After the addition was complete, the system was gradually restored to room temperature and stirred for 5 hours. HPLC detection confirmed that the borylation reaction was complete. After the reaction was completed, 1N dilute hydrochloric acid was added dropwise to the system and the pH of the system was adjusted to about 7.0. The aqueous layer was extracted three times with isobutyl acetate (10 mL) and the organic phase was combined. The organic phase was dried and rotary evaporated to obtain the corresponding 4- 10 The crude B-boryl-N-acetyl-phenylalanine was directly carried into the next step without purification.

[0139] 2) Add the 4- 10The crude B-boryl-N-acetyl-phenylalanine, acetone (20 mL) and hydrochloric acid (7.5 g, 76.7 mmol, 37 wt%) were heated to 60° C. and then stirred and refluxed for 2 hours. The complete consumption of the starting materials was confirmed by HPLC monitoring. After the reaction was completed, acetone was removed as much as possible by rotary evaporation, and the aqueous phase was washed three times with isobutyl acetate (10 mL) and the aqueous phase was retained. Then, the beaker containing the aqueous phase was placed in an ice-water bath, and 3N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to about 6.0. After standing for 2 hours, it was filtered, and the filter cake was washed with a small amount of methanol. The filter cake was slurried with dichloromethane (10 mL) to finally obtain pure 4- 10 1.2 g of B-boric acid-L-phenylalanine was obtained, with a comprehensive yield of 44.9% and a boron atom utilization rate of 42%.

[0140] Comparative Example 1

[0141] This comparative example provides a 4- 10 The production method of B-boric acid-L-phenylalanine, the reaction formula is as follows:

[0142]

[0143] The specific steps are as follows: 1) adding 4-iodo-N-Boc-phenylalanine (5.0 g, 12.8 mmol) and THF (10 mL) to a dry reactor A, stirring and dissolving, and then cooling at -30 ° C. n-Butyl lithium solution (13.3 mL, 31.9 mmol, 2.4 M n-hexane solution) was added dropwise to the system, and the system temperature was controlled not to exceed 25 ° C. After stirring for 5 hours, the reaction degree was confirmed by HPLC detection; then, a THF solution of 4,4,5,5-tetraethyl-1,3,2-dioxaborolane (2.47 g, 13.4 mmol, dissolved in 10 mL) was added dropwise to the system. After the addition was complete, the system was gradually restored to room temperature and stirred for 5 hours. HPLC detection confirmed that the borylation reaction was complete. After the reaction was completed, 1N dilute hydrochloric acid was added dropwise to the system and the pH of the system was adjusted to about 7.0. The aqueous layer was extracted three times with isobutyl acetate (10 mL) and the organic phase was combined. The organic phase was dried and rotary evaporated to obtain the corresponding 4- 10 The crude B-boryl-N-Boc-phenylalanine was directly carried into the next step without purification.

[0144] 2) Add the 4- 10Crude B-boryl-N-Boc-phenylalanine, acetone (20 mL) and hydrochloric acid (7.5 g, 76.7 mmol, 37 wt%) were heated to 60° C. and then stirred and refluxed for 2 hours. HPLC monitoring confirmed that the raw materials were completely consumed. After the reaction was completed, acetone was removed as much as possible by rotary evaporation, and the aqueous phase was washed three times with isobutyl acetate (10 mL) and the aqueous phase was retained. Then, the beaker containing the aqueous phase was placed in an ice-water bath, and 3N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to about 6.0. After standing for 2 hours, it was filtered, and the filter cake was washed with a small amount of methanol. The filter cake was slurried with dichloromethane (10 mL) to finally obtain pure 4- 10 0.85 g of B-boric acid-L-phenylalanine was obtained, with a comprehensive yield of 31.8% and a boron atom utilization rate of 30%.

[0145] The above description of the embodiments is intended to facilitate understanding and use of the invention by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without requiring inventive effort. Therefore, the present invention is not limited to the above-described embodiments. Improvements and modifications made by those skilled in the art based on the disclosure of the present invention, without departing from the scope of the present invention, should be within the scope of protection of the present invention.

Claims

1. A 4- 10 The method for producing B-boric acid-L-phenylalanine is characterized in that: The following steps are involved: A. Add a strong base and a Turbo Grignard reagent to a 4-halogenated phenylalanine derivative to react, then add a diol ester borane to continue the reaction to obtain a 4-boryl-phenylalanine derivative; B. Acid hydrolysis of 4-boryl-phenylalanine derivatives to obtain 4- 10 B-Borate-L-Phenylalanine.

2. The 4- 10 The method for producing B-boric acid-L-phenylalanine is characterized in that: In step A, the 4-halogeno-phenylalanine derivative has a structure shown in the following formula (I): Among them, R 1 is halogen; R 2 is an amino protecting group, specifically selected from tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, acetyl, trifluoroacetyl, benzoyl, benzyl, 4-methoxybenzyl; PG is a protected H atom form and a protected acetal form, and the acetal form is selected from carbon acetal, silicon acetal and boron complex.

3. The 4- 10 The method for producing B-boric acid-L-phenylalanine is characterized in that: The R 1 is any one of chlorine, bromine and iodine; 2 It is any one of tert-butyloxycarbonyl, trimethylsilylethoxycarbonyl and benzyloxycarbonyl.

4. The 4-boron atom with high boron atom utilization rate according to claim 1 10 The method for producing B-boric acid-L-phenylalanine is characterized in that: In step A, the strong base is selected from at least one of a first strong base and a second strong base; The first strong base comprises at least one of sodium hydride, sodium hydroxide, sodium carbonate, sodium amide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium hydride, potassium hydroxide, potassium carbonate, potassium amide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, lithium hydride, lithium hydroxide, lithium carbonate, lithium amide, lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, calcium hydride, calcium hydroxide, calcium carbonate, calcium amide, calcium methoxide, calcium ethoxide, calcium isopropoxide, calcium tert-butoxide, magnesium hydride, magnesium hydroxide, magnesium carbonate, magnesium amide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, and magnesium tert-butoxide; The second strong base includes at least one of isopropyl lithium, butyl lithium, hexyl lithium, bis(trimethylsilyl)amide lithium, phenyl lithium, 2,2,6,6-tetramethylpiperidinium lithium, isopropyl sodium, butyl sodium, hexyl sodium, bis(trimethylsilyl)amide sodium, phenyl sodium, 2,2,6,6-tetramethylpiperidinium sodium, isopropyl potassium, butyl potassium, hexyl potassium, bis(trimethylsilyl)amide potassium, phenyl potassium, 2,2,6,6-tetramethylpiperidinium potassium, isopropyl calcium, butyl calcium, hexyl calcium, bis(trimethylsilyl)amide calcium, phenyl calcium, 2,2,6,6-tetramethylpiperidinium calcium, isopropyl magnesium, butyl magnesium, hexyl magnesium, bis(trimethylsilyl)amide magnesium, phenyl magnesium, and 2,2,6,6-tetramethylpiperidinium magnesium.

5. The 4-boron atom with high boron atom utilization rate according to claim 4 10 The method for producing B-boric acid-L-phenylalanine is characterized in that: The strong base is selected from at least one of sodium hydride, butyl lithium, isopropyl lithium, lithium bis(trimethylsilyl)amide, and 2,2,6,6-tetramethylpiperidinium lithium.

6. The 4- 10 The method for producing B-boric acid-L-phenylalanine is characterized in that: In step A, the Turbo Grignard reagent is selected from at least one of i-PrMgCl·LiCl, s-BuMgCl·LiCl, c-HexMgCl·LiCl, (s-Bu)2Mg·2(LiCl), (n-Bu)2MgCl·2LiCl, s-BuMg(Ot-Bu)·LiCl, and s-BuMg(OMe)·LiCl.

7. The 4-( ...boron)-atom) with high boron atom utilization rate according to claim 1 10 The method for producing B-boric acid-L-phenylalanine is characterized in that: In step A, the diol ester borane has any one of the following structures: (IV) to (XIII), wherein the boron atom is represented by 11 B or 10 B:

8. The 4-( ...boron)-atom) with high boron atom utilization rate according to claim 7. 10 The method for producing B-boric acid-L-phenylalanine is characterized in that: The diol ester borane has a structure of any one of formula (IV) to formula (VII), formula (IX), and formula (X).

9. The 4-( ...boron)-atom) with high boron atom utilization rate according to claim 1 10 The method for producing B-boric acid-L-phenylalanine is characterized in that: In step A, the molar ratio of the 4-halogenated phenylalanine derivative and the strong base is 1.0:0.0~5.0 equivalents, the molar ratio of the 4-halogenated phenylalanine derivative and the Turbo Grignard reagent is 1.0:1.0~10.0 equivalents, and the molar ratio of the 4-halogenated phenylalanine derivative and the diol ester borane is 1.0:1.0~10.0 equivalents.

10. The 4-( ...boron)-atom)-containing compound with high boron atom utilization rate according to claim 1 10 The method for producing B-boric acid-L-phenylalanine is characterized in that: In step B, hydrochloric acid is added during the acidic hydrolysis; the molar ratio of the 4-halogenated-phenylalanine derivative to the hydrochloric acid is 1.0:3.0-100.0 equivalents.

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