18F-BPA manufacturing method and intermediates

Abstract

To provide a method for preparing 18F-BPA and an intermediate, which can obtain high-purity 18F-BPA, simplifies synthesis steps after 18F-BPA labeling, and is easy to operate and efficient.SOLUTION: In the formula of an intermediate I, R1 and R2 each represent a halogen, or R1 and R2 each represent a boric acid group or a substituent hydrolyzable to the boric acid group, R3 and R4 each represent hydrogen and an amino-protecting group, or form an imino group together with an amino group for protecting the amino group, and R5 represents hydrogen or a carboxyl-protecting group.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to the fields of medicine and chemical synthesis, specifically: 18 The present invention relates to a method for producing F-BPA and intermediates thereof. [Background technology]

[0002] Malignant tumors are serious diseases that seriously harm human health and life. Currently, the treatment of malignant tumors is mainly performed by radiation therapy or chemotherapy. Boron Neutron Capture Therapy (BNCT) is to destroy cancer cells by nuclear reactions occurring in tumor cells. Boron ( 10 B) Taking advantage of the property that the contained agent has a high capture cross section for thermal neutrons, 10 B(n, α) 7 Li neutron capture and fission reactions produce two heavy charged particles, 4 He and 7 Li is generated. The average energy of the two charged particles is about 2.33 MeV, and they have the characteristics of high linear energy transfer (LET) and short radiation distance. The linear energy transfer and radiation distance of the α particles are 150 keV / μm and 8 μm, respectively. 7 For Li heavy charged particles, it is 175 keV / μm, 5μm, and the total radiation distance of the two particles is approximately equivalent to the size of one cell, so the radiation damage to the organism can be limited to the cellular level, and when the boron-containing drug is selectively collected in the tumor cells, it can be combined with a suitable neutron source to achieve the purpose of locally killing the tumor cells, on the premise that it does not cause too much damage to normal tissues. The effect of boron neutron capture therapy is determined by the concentration of the boron-containing drug and the number of thermal neutrons at the location of the tumor cells, so it is also called binary radiation cancer therapy, and therefore, in addition to the development of neutron sources, the development of boron-containing drugs plays an important role in the research of boron neutron capture therapy. ( 10 B) Borono-L-phenylalanine (4-( 10B) borono-L-phenylalanine, L- 10 BPA is a boron-containing drug used in cancer treatment by BNCT, and has a high therapeutic effect against various malignant tumors such as glioblastoma multiforme and melanoma. The formulation of a BNCT treatment plan is 18 Guided by the tumor targeting results of F-BPA (2-fluoro-4-borono-L-phenylalanine), a positron-emitting nuclide 18 There is a need to use F-labeled BPA in combination with positron emission tomography (PET) to diagnose brain tumors and other types of solid tumors.

[0003] CN105916836A discloses a method for producing 2-fluoro-4-borono-L-phenylalanine and a precursor of 2-fluoro-4-borono-L-phenylalanine. 18 F ions replace the leaving group on the benzene ring, 18 After obtaining the F-labeled halogen-substituted phenylalanine compound, the compound was subjected to a coupling reaction to obtain the phenylalanine compound. 18 F-BPA is obtained. In CN105348309B, 18 After labeling with F, the aldehyde group on the benzene ring reacts with the benzoxazolinone to form 18 F-BPA is obtained. In CN102887913B, 18 F ions replace the nitro group on the benzene ring, 18 After obtaining the F-labeled iodine-substituted phenylalanine compound, the product was subjected to a coupling reaction. 18 F-BPA is obtained. 18 Since a boric acid ester substitution reaction is carried out after labeling with F, there are many reaction steps and the production time is long.

[0004] 18 Since the half-life of F is about 110 min, 18How to simplify the manufacturing steps and shorten the manufacturing time after labeling with F is a very meaningful and challenging research, which is related to the radiochemical yield of the synthesis and the limitation of application. Therefore, the development of a manufacturing method that meets clinical requirements, is simple, highly efficient, has mild reaction conditions, and has a high yield. 18 This is very important for the application of F-BPA. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention relates to 2-fluoro-4-boronophenyl-L-phenylalanine ( 18 The present invention aims to provide a method for producing F-BPA and FBPA, and an intermediate thereof. 18 The synthesis method of F-BPA is as follows: 18 It simplifies the synthetic steps after labeling with F, which is simple and efficient, has high yields, high product purity, and improves the radiochemical yield of the synthesis. [Means for solving the problem]

[0006] According to a first aspect of the present invention, there is provided a compound having the following structure: 18 The manufacturing method of F-BPA is as follows: [ka] It involves using an intermediate I having the structure of formula I, [ka] In the formula, R 1 , R 2 is a halogen, or R 1 , R 2 is a boric acid group or a substituent that can be hydrolyzed to a boric acid group, and R 3 , R 4 are hydrogen and a protecting group for an amino group, or together with an amino group form an imino group that protects an amino group, and R 5 is a protecting group for hydrogen or a carboxyl group.

[0007] In another preferred embodiment, the intermediate I includes intermediates I-1 and I-2, The intermediate I-1 has the structure of formula I-1: [ka] The intermediate I-2 has the structure of formula I-2: [ka] In the formula, X 1 , X 2 is a halogen, and preferably, 1 , X 2 is chlorine, bromine or iodine, R 10 and R 20 are OH or represent substituents which, together with the boron atom to which they are attached, can be hydrolyzed to a boronic acid group; R 3 and R 4 are hydrogen and a protecting group for an amino group, or together with an amino group form an imino group that protects an amino group, and R 5 is a protecting group for hydrogen or a carboxyl group.

[0008] In another preferred embodiment, R 3 and R 4 The protecting group for the amino group includes an alkoxycarbonyl protecting group, an acyl protecting group, and an alkyl protecting group. 3 and R 4 further includes, as a protecting group for an amino group, a substituent selected from the group consisting of a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a fluorenylmethyloxycarbonyl group, an allyloxycarbonyl group, a trimethylsilylethoxycarbonyl group, a methoxycarbonyl group or an ethoxycarbonyl group, a phthaloyl group, a p-toluenesulfonyl group, a trifluoroacetyl group, an ortho(para)nitrobenzenesulfonyl group, a piperoyl group, a benzoyl group, a triphenylmethyl group, a 2,4-dimethoxybenzyl group, a p-methoxybenzyl group, and a benzyl group.

[0009] In another preferred embodiment, R 3 and R 4 is a protecting group for an amino group, which forms a C=N bond together with N, and is preferably -NR 3 R 4 teeth [ka] It is.

[0010] In another preferred embodiment, the substituent hydrolyzable to the boric acid group is a borate ester group. 10 and R 20 is a boronic acid pinacol ester group. The boron in this application is preferably boron-10.

[0011] In another preferred example, the protective group for the carboxyl group is a substituted or unsubstituted C1-C20 alkyl group. The substituents include a phenyl group, a halogen, a nitro group, a hydroxy group, and a methoxy group, and preferably the protective group for the carboxyl group is a C1-C10 alkyl group, a phenyl group, or a benzyl group. Preferably, the protective group for the carboxyl group includes a substituted or unsubstituted C1-C20 alkyl group, and the substituents include a phenyl group, a halogen, a nitro group, a hydroxy group, and a methoxy group, and preferably the C1-C10 alkyl group, a phenyl group, or a benzyl group. Preferably, the protective group for the carboxyl group further includes a methyl group, an ethyl group, an isopropyl group, a t-butyl group, a diphenylmethyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a 4-benzylpyridine group, a trichloroethyl group, a methylthioethyl group, a p-toluenesulfonylethyl group, a p-nitrobenzylthioxoethyl group, a phenyl group, or a benzyl group.

[0012] In another preferred embodiment, the intermediate I is selected from the following compounds: [ka]

[0013] In another preferred embodiment, the process comprises the steps of: 18 React with F ions 18 obtaining a compound substituted with F, [ka] In the formula, R 10 and R 20 are OH or represent substituents which, together with the boron atom to which they are attached, can be hydrolyzed to a boronic acid group; R 3 and R 4 are hydrogen and a protecting group for an amino group, or together with an amino group form an imino group that protects an amino group, and R 5 is a protecting group for hydrogen or a carboxyl group.

[0014] In another preferred embodiment, the method further comprises the steps of: 18 Deprotecting the protecting group in the compound substituted with F to form the compound 18 Further comprising obtaining F-BPA. [ka]

[0015] In another preferred embodiment, the intermediate I-2 and 18 The reaction of F ions further includes the use of a copper catalyst, preferably the copper catalyst is Cu(OTf) 2 Py 4 or Cu(OTf) 2 Includes.

[0016] In another preferred embodiment, the intermediate I-2 and 18 The reaction temperature of the F ions is 20 to 150°C, and preferably 100 to 130°C.

[0017] In another preferred embodiment, the intermediate I-2 and 18 Solvents used for the reaction of F ions include water, methanol, DMF, DMA, DMSO, acetonitrile, n-butanol, ethanol, dichloromethane, etc., or any mixture thereof.

[0018] In another preferred embodiment, intermediate I-1 is reacted with boronic acid or a boronic acid ester to obtain intermediate I-2, [ka] In the formula, X 1 , X 2 is a halogen, and preferably, 1 , X 2 is chlorine, bromine or iodine, R 10 and R 20 are OH or represent substituents which, together with the boron atom to which they are attached, can be hydrolyzed to a boronic acid group; R 3 and R 4 are hydrogen and a protecting group for an amino group, or together with an amino group form an imino group that protects an amino group, and R 5 is a protecting group for hydrogen or a carboxyl group.

[0019] In another preferred embodiment, the intermediate I-1 and boronic acid or a boronic acid ester are reacted in a nitrogen atmosphere.

[0020] In another preferred example, the intermediate I-1 and boric acid or a borate ester are reacted under conditions of 20 to 100°C, preferably 50 to 100°C.

[0021] There is no particular limitation on the palladium catalyst. Preferably, the palladium catalyst is tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(tri-o-tolylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethane palladium dichloride, or compositions thereof.

[0022] There is no particular limitation on the borate ester.Preferably, the borate ester is selected from the group consisting of bis(pinacolato)diboron, bis(catecholato)diboron, bis(3,3-dimethyl-2,4-pentanediol)boronic acid ester, triethanolamineboronic acid ester, trimethyl borate, triisopropyl borate, triethyl borate, tributyl borate, bis(neopentylglycolato)diboron, or a combination thereof.

[0023] In another preferred embodiment, the method further comprises chiral separation of intermediate I-1 to obtain compound I-1a in L form and compound I-1b in D form, followed by reaction with boronic acid or a boronic acid ester, respectively. [ka]

[0024] In another preferred embodiment, the process comprises: i) reacting intermediate II with intermediate III to obtain intermediate I-1; [ka] In the formula, X 1 , X 2 , X 3 are each halogen, and preferably, 1 , X 2 , X 3 is chlorine, bromine or iodine, R 3 and R 4are each independently a hydrogen atom and a protecting group for an amino group, or together with an amino group form an imino group that protects an amino group, R 5 is a protecting group for hydrogen or a carboxyl group.

[0025] In another preferred embodiment, the intermediate III is [ka] and the intermediate I-1 is [ka] Wherein, X 1 , X 2 is a halogen, and preferably, 1 , X 2 is chlorine, bromine or iodine, R 5 is a protecting group for hydrogen or a carboxyl group.

[0026] In another preferred embodiment, the method comprises deprotecting the amino group in the intermediate I-1 by hydrolysis under acidic conditions to form Boc 2 O under basic conditions to protect the amino group in intermediate I-1 with Boc to give compound I-2. [ka] and then reacting with boronic acid or a boronic acid ester, said reaction being preferably carried out at room temperature, and the preferred R 5 is a C1 to C10 alkyl group.

[0027] Intermediate I according to the second aspect of the present invention has the following structure: [ka] In the formula, R 1 , R 2 is a halogen, or R 1 , R 2is a boric acid group or a substituent hydrolyzable to a boric acid group, R 3 , R 4 are a protecting group for hydrogen and an amino group, respectively, or form an imino group that protects the amino group together with the amino group, R 5 is a protecting group for hydrogen or a carboxyl group.

[0028] In another preferred embodiment, the intermediate I includes intermediates I-1 and I-2, and the intermediate I-1 has the structure of formula I-1: [ka] The intermediate I-2 has the structure of formula I-2: [ka] In the formula, X 1 , X 2 is a halogen, B represents boron, preferably boron-10, and R 10 and R 20 are OH or represent substituents which, together with the boron atom to which they are attached, can be hydrolyzed to a boronic acid group; R 3 and R 4 are hydrogen and a protecting group for an amino group, or together with an amino group form an imino group that protects an amino group, and R 5 is a protecting group for hydrogen or a carboxyl group.

[0029] In another preferred embodiment, the hydrolyzable substituent on the boronic acid group is a boronic acid ester group, preferably a boronic acid pinacol ester group, R 3 and R 4 includes an alkoxycarbonyl protecting group, an acyl protecting group, and an alkyl protecting group; R 5 includes a substituted or unsubstituted C1 to C20 alkyl group, and is preferably a t-butyl group.

[0030] In another preferred embodiment, the intermediate I is selected from the following compounds: [ka]

[0031] A use of the intermediate I according to the second aspect of the present invention, which relates to a third aspect of the present invention, comprises: 18 The present invention relates to the production of F-BPA, 18 F-BPA is [ka] It has a structure.

[0032] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (for example, in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described here one by one due to space limitations. [Brief description of the drawings]

[0033] [Figure 1] 1 is a proton nuclear magnetic resonance spectrum of N,N-di(tert-butoxycarbonyl)-2,4-di(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenylalanine tert-butyl ester prepared in Example 6. [Diagram 2] 1 is the 18F-BPA radioactive HPLC spectrum of the present invention. [Diagram 3] 1 is a radioactive HPLC spectrum of the 18F-BPA of the present invention after mixing with standard 19F-BPA. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] As a result of extensive investigation, the present inventors have found that 18 The present invention provides a method for producing F-BPA by the use of a phenylalanine intermediate substituted with a diboronic acid pinacol ester group, the diboronic acid pinacol ester group being ortho to the alanine group. 18 By substituting F,18 The method can provide F-BPA. 18 After labeling with F 18 The present invention simplifies the steps of F-BPA synthesis, and is simple, efficient, has a high yield, and is highly pure, and improves the radiochemical yield of the synthesis.

[0035] (term) Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent applications, and disclosure materials cited throughout this specification are incorporated herein by reference in their entirety.

[0036] It should be understood that the above summary and the following detailed description are illustrative and for the purpose of interpretation only, and do not limit the subject matter of the present invention. In this specification, the singular includes the plural, unless otherwise specified. Please note that in this specification, the singular includes the plural of what is referred to, unless otherwise specified. Please also note that the terms "or" and "or" mean "and / or" unless otherwise specified. In addition, the term "comprises" and other forms, such as "including", "including", "containing", are not limiting.

[0037] When a substituent is described by a general chemical formula written from left to right, the substituent also includes the chemically equivalent substituent that would result if the structural formula were written from right to left. For example, -CH 2 O-OCH 2 - is equivalent to

[0038] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are hereby incorporated by reference in their entirety.

[0039] Except as set forth above, as used in the specification and claims of this application, the following terms have the following meanings unless otherwise stated.

[0040] In this application, the term "halogen" means fluorine, chlorine, bromine or iodine. "F" refers to fluorine, including radioactive and non-radioactive fluorine, for example: 18 F, 19 F, preferably 18 F. "B" refers to boron, including radioactive and non-radioactive boron, and preferably 10 B. "N" is nitrogen. A "nitro group" is -NO 2 An "amino group" refers to the -NH 2 A "boronic acid group" refers to the -B(OH) group. 2 Refers to the base.

[0041] As used herein, the term "alkyl group" as a group or part of another group (e.g., groups such as halogen-substituted alkyl groups) refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing no unsaturated bonds, having 1 to 10 carbon atoms, and attached to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like. The term "C1-C10 alkyl group" refers to an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and pentyl.

[0042] Preferably, the inert solvent is selected from the group consisting of toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran dichloromethane, trichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a composition thereof. More preferably, the inert solvent is a mixed solvent of benzene and water.

[0043] The term "substituent hydrolyzable to a boric acid group" means that the substituent becomes a boric acid group (-B(OH)) after hydrolysis. 2 ), for example, represents the formation of a borate ester group, and the substituent is [ka] [ka] [ka] [ka] [ka] [ka] [ka] and preferably a boronic acid pinacol ester group.

[0044] In the present invention, R 3 and R 4 may be a protecting group for an amino group, including, but not limited to, an alkoxycarbonyl protecting group, an acyl protecting group, and an alkyl protecting group; R 3 and R 4 may be one which protects the amino group by forming an imide (C=N) with N, for example, [ka] Both of the above two types of protecting groups should be within the scope of the "protecting group for amino group" of the present invention. The alkoxycarbonyl protecting group includes, but is not limited to, a benzyloxycarbonyl group (Cbz), a tert-butoxycarbonyl group (Boc), a fluorenylmethyloxycarbonyl group (Fmoc), an allyloxycarbonyl group (Alloc), a trimethylsilylethoxycarbonyl group (Teoc), a methoxycarbonyl group or an ethoxycarbonyl group. The acyl protecting group includes, but is not limited to, a phthaloyl group (Pht), a p-toluenesulfonyl group (Tos), a trifluoroacetyl group (Tfa), an ortho(para)nitrobenzenesulfonyl group (Ns), a piperoyl group, and a benzoyl group. The alkyl protecting group includes, but is not limited to, a triphenylmethyl group (Trt), a 2,4-dimethoxybenzyl group (Dmb), a p-methoxybenzyl group (PMB), and a benzyl group (Bn).

[0045] The term "protective group for a carboxyl group" refers to a protecting group that forms an ester group, an amide or a hydrazide with a carboxyl group, and includes, but is not limited to, an alkyl group, a phenyl group, and an amino group substituted with an alkyl group. The "alkyl group" is preferably a straight-chain or branched-chain-containing alkyl group substituted or unsubstituted with a substituent having 1 to 20 carbon atoms, such as a methyl group, an ethyl group, an isopropyl group, a t-butyl group, a diphenylmethyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a 4-benzylpyridine group, a trichloroethyl group, a methylthioethyl group, a p-toluenesulfonylethyl group, and a p-nitrobenzylthioxoethyl group.

[0046] As used herein, "optionally" or "optionally" means that the described event or circumstance may or may not occur, and the statement includes both cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, an "optionally substituted aryl group" means that the aryl group is substituted or unsubstituted, and the statement includes both substituted and unsubstituted aryl groups.

[0047] The present invention covers various stereoisomers and mixtures thereof, where "stereoisomer" refers to compounds consisting of the same atoms and bonded by the same bonds, but having different three-dimensional structures. All tautomeric forms of the compounds of the present invention are also included within the scope of the present invention, where "tautomer" refers to an isomer formed when a proton is transferred from one atom of a molecule to another atom of the same molecule.

[0048] The intermediate compounds of the present invention contain chiral carbon atoms, and therefore can produce enantiomers, non-enantiomers and other stereoisomers. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, their racemic and optically pure forms. In the preparation of the compounds of the present invention, racemic, non-enantiomers or enantiomers can be selected as raw materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, and can be resolved using conventional techniques such as crystallization and chiral chromatography. The "intermediate" of the present invention has two types of structures, an L-phenylalanine structure and a D-phenylalanine structure, both of which are within the scope of protection of the present invention.

[0049] 18 Manufacturing method of F-BPA The present invention relates to 18 The novel method for producing F-BPA can be realized, for example, by the following example, but is not limited to the exemplary method. The protecting groups of the amino group and carboxyl group and the borate ester group used in the following reaction scheme can be appropriately changed, and are not limited to the exemplary method.

[0050] The method comprises the steps of: 18 React with F ions 18 Obtaining a compound substituted with F; [ka] The above 18The protecting groups in the F-substituted compound are deprotected, for example, by hydrolyzing the protecting groups of the amino and carboxyl groups and the borate ester group, to obtain the compound. 18 and obtaining F-BPA. [ka]

[0051] For the reaction of each step, the reaction temperature can be appropriately selected depending on the solvent, starting material, reagents, etc., and the reaction time can be appropriately selected depending on the reaction temperature, solvent, starting material, reagents, etc. After the reaction of each step is completed, the target compound can be subjected to steps such as separation and purification from the reaction system according to conventional methods such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. If the target compound does not affect the next reaction, it can be directly used in the next reaction without separation and purification.

[0052] Intermediate I 18 In the synthesis step of F-BPA, 18 F ion ([ 18 F]F - is H with a proton beam 2 18 Shocking O, 18 It can be obtained by O(p,n) reaction or by methods known in the art. 18 F ions were captured on an ion exchange column and K2.2.2 / K 2 CO 3 The mixture is eluted, dehydrated and dried, and then used for labeling reaction. 18 The mixture is reacted with F ions, purified by a cation column, dried, hydrolyzed, and the protecting groups of the amino and carboxyl groups are removed to obtain the above-mentioned 18F-BPA is obtained. Reagents used include hydrogen fluoride and potassium fluoride. Solvents used include water, methanol, DMF, DMA, DMSO, acetonitrile, n-butanol, ethanol, dichloromethane, etc., or any mixed solvent thereof. The reaction temperature is preferably 20 to 150°C, more preferably 100 to 130°C. The reaction time is preferably 5 minutes to 1 hour, more preferably 10 to 30 minutes. The dehydration and drying may be performed by adding a dry organic solvent and removing water by azeotropy, and usable organic solvents include, but are not limited to, acetonitrile, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), or any combination thereof. In a preferred embodiment, intermediate I and 18 In the reaction of F ions, a copper catalyst may be added. The copper catalyst that can be used is Cu(OTf) 2 Py 4 or Cu(OTf) 2 , or combinations thereof.

[0053] In addition, the intermediate I of the present invention 18 F-BPA includes all of its optical isomers, including isomers having an L-phenylalanine structure and isomers having a D-phenylalanine structure. For example, 18 F-BPA has an L-phenylalanine structure 18 FL-BPA or D-phenylalanine structure 18 In the above-mentioned production method of the present invention, the intermediate I may be subjected to chiral separation to obtain a single compound, which is then reacted. Alternatively, the intermediate I may be subjected to a direct reaction without chiral separation to obtain a single compound, which is then reacted. 18 F-BPA may be obtained.

[0054] The present invention will be further described below with reference to specific examples. It should be understood that the following description is merely the most preferred embodiment of the present invention and should not be considered as a restriction on the scope of protection of the present invention. With a full understanding of the present invention, the experimental methods not specified in the following examples are usually carried out according to general conditions or according to the conditions proposed by the manufacturer, and those skilled in the art can make non-essential changes to the technical means of the present invention, and such changes should be considered as falling within the scope of protection of the present invention. Unless otherwise specified, percentages and parts are weight percentages and weight parts. EXAMPLES

[0055] Preparation of N-diphenylmethylene-2,4-dibromophenylalanine tert-butyl ester Dissolve N-diphenylmethylene-glycine tert-butyl ester (40 g, 135.42 mmol, 1 eq), 1,4-dibromobenzyl bromide (44.53 g, 135.42 mmol, 1 eq), and tetrabutylammonium bromide (TBAB, 436.55 mg, 1.35 mmol, 0.01 eq) in 300 mL of toluene, add 80 mL of aqueous potassium hydroxide (100.00 g, 1.78 mol, 13.16 eq). Stir at 25 °C for 12 hours until the reaction is complete. Dilute the reaction mixture with 100 mL of ethyl acetate, extract with 400 mL (200 mL x 2) of ethyl acetate, mix the organic phases, wash with 600 mL (300 mL x 2) of saturated saline, and add Na 2 SO 4 The solid was obtained by filtration and the crude product was separated by column chromatography (petroleum ether / ethyl acetate=100:1-20:1) to obtain 15 g of product.

[0056] LCMS:MS(M+H + )=544.0 1 H NMR: 400MHz, CDCl 3 δ7.56-7.46(m,3H), 7.35-7.16(m,7H), 7.01(d,J=8.2Hz,1H), 6.59(br d,J=6.8 Hz,2H), 4.23(dd,J=4.2,9.5 Hz,1H), 3.31(dd,J=4.0,13.4 Hz,1H), 3.11(dd,J=9.6,13.5 Hz,1H), 1.41-1.28(m,9H). [ka] EXAMPLES

[0057] Preparation of N-tert-butoxycarbonyl-2,4-dibromophenylalanine tert-butyl ester Dissolve N-diphenylmethylene-2,4-dibromophenylalanine tert-butyl ester (30 g, 55.22 mmol, 1 eq) in THF (70 mL), add 20 mL of aqueous citric acid (31.83 g, 165.66 mmol, 31.86 mL, 3 eq), and stir at 25 °C for 12 h. Add 50 mL of Na 2 CO 3 (29.26g, 276.10mmol, 5 eq) in water and Boc 2 Add 13.26 g (60.74 mmol, 13.95 mL, 1.1 eq) of HO and continue stirring for 4 h. When the reaction is complete, extract the reaction mixture with 400 mL (200 mL x 2) of ethyl acetate, combine the organic phases and wash with 400 mL (200 mL x 2) of saturated saline, and add 10 mL of NaCl. 2 SO 4 The solid is obtained by filtration and the crude product is separated by column chromatography (petroleum ether / ethyl acetate=100:1-10:1) to give 19.6g of product with a yield of 73.48% and a purity of 99.2%.

[0058] LCMS:MS(M-155 + )=323.9 1 H NMR: 400MHz, CDCl 3 δ7.72(d,J=1.5 Hz,1H,7.37(dd,J=1.8,8.1 Hz,1H), 7.13(br d,J=8.1 Hz,1H), 5.06(br d,J=8.3 Hz,1H), 4.59-4.38(m,1H), 3.23(dd,J=5.9,13.9 Hz,1H), 3.00(br dd,J=8.6,13.8 Hz,1H), 1.40(br d,J=16.6 Hz,17H). [ka] EXAMPLES

[0059] Chiral separation of N-tert-butoxycarbonyl-2,4-dibromophenylalanine tert-butyl ester 19.6 g of N-tert-butoxycarbonyl-2,4-dibromophenylalanine tert-butyl ester was subjected to SFC (chromatographic column: DAICEL CHIRALPAK AY (250 mm * 50 mm, 10 um), mobile phase: [0.1% NH 3 H 2 O 2 MEOH] to give 9.1 g of product in 46.84% yield with 97.8% purity and 9.2 g of product in 48.18% yield with 99.5% purity. [ka] EXAMPLES

[0060] Preparation of N-tert-butoxycarbonyl-2,4-di(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenylalanine tert-butyl ester N-tert-butoxycarbonyl-2,4-dibromo-phenylalanine tert-butyl ester (7.50 g, 15.6 mmol, 1.00 eq), pinacol diboronic acid ester (19.8 g, 78.2 mmol, 5.00 eq), KOAc (6.14 g, 62.6 mmol, 4.00 eq), Pd(dppf)Cl2 (1.15 g, 1.57 mmol, 0.10 eq) and dioxane (75.0 mL) are stirred at 90 °C under nitrogen atmosphere for 1 h. When the reaction is complete, it is filtered, 200 mL of water is added, the reaction mixture is extracted with 300 mL (100 mL x 3) of ethyl acetate, the organic phases are combined and washed with 200 mL (100 mL x 2) of saturated saline, and then washed with Na 2 SO 4 Dry at rt and filter to obtain a solid. Purify the crude product by HPLC to give 6.5 g of product with a purity of 96.3%.

[0061] LCMS:MS(M+H + -156)=418.0 1 H NMR: 400MHz, CDCl 3 8.24(s,1H), 7.84(d,J=7.6,1H), 7.30(d,J=7.6,1H), 5.90(d,J=8.4,1H), 4.24-4.1 9(m,1H), 3.24-3.19(m,2H), 1.47(s,9H), 1.39(s,12H), 1.34(s,12H), 1.32(s,9H). [ka] EXAMPLES

[0062] Preparation of N-tert-butoxycarbonyl-2,4-di(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenylalanine tert-butyl ester O-tert-butoxycarbonyl-2,4-dibromo-phenylalanine tert-butyl ester (7.00 g, 14.6 mmol, 1.00 eq), pinacol diboronic acid ester (18.5 g, 73.0 mmol, 5.00 eq), KOAc (5.73 g, 58.4 mmol, 4.00 eq), Pd(dppf)Cl 2(5.73 g, 58.4 mmol, 4.00 eq) and dioxane (70.0 mL) are stirred at 90 °C under nitrogen atmosphere for 3 h. When the reaction is complete, it is filtered, 200 mL of water is added, the reaction mixture is extracted with 300 mL (100 mL x 3) of ethyl acetate, the organic phases are combined and washed with 200 mL (100 mL x 2) of saturated saline, and then washed with Na 2 SO 4 Dry at 40° C. and filter to obtain a solid. Purify the crude product by HPLC to give 5.37 g of product with a purity of 97.35%.

[0063] LCMS:MS(M-100-55+H + )=418.3 1 HNMR: 400MHz, CDCl 3 δ1.31-1.35(m,21 H), 1.39(s,12 H), 1.47(s,9 H), 3.16-3.29(m,2 H), 4.19-4.26(m,1 H), 5.89(br d,J=8.40 Hz,1 H), 7.30(d,J=8.00 Hz,1 H), 7.84(dd,J=7.60,1.47 Hz,1 H), 8.24(s,1 H) [ka] EXAMPLES

[0064] Preparation of N,N-di(tert-butoxycarbonyl)-2,4-di(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenylalanine tert-butyl ester N-tert-butoxycarbonyl-2,4-dibromo-phenylalanine tert-butyl ester (7.00 g, 14.6 mmol, 1.00 eq), pinacol diboronic acid ester (18.5 g, 73.0 mmol, 5.00 eq), KOAc (5.73 g, 58.4 mmol, 4.00 eq), Pd(dppf)Cl 2(5.73 g, 58.4 mmol, 4.00 eq) and dioxane (70.0 mL) are stirred at 90 °C under nitrogen atmosphere for 3 h. When the reaction is complete, it is filtered, 200 mL of water is added, the reaction mixture is extracted with 300 mL (100 mL x 3) of ethyl acetate, the organic phases are combined and washed with 200 mL (100 mL x 2) of saturated saline, and then washed with Na 2 SO 4 The solid is dried at 40° C. and filtered to obtain a solid. The crude product is purified by HPLC to obtain 5.37 g of product with a purity of 97.35%. See FIG. 1 for the proton nuclear magnetic resonance spectrum. [ka] EXAMPLES

[0065] 18 Production of F-BPA Accelerated protons are H 2 18 Irradiate with O, 18 O(p,n) reaction 18 Obtaining F ions, 18 F ions were captured on an ion exchange column and K2.2.2 / K 2 CO 3 The compound obtained in Example 5 was dissolved in a DMA solution and then dried and used for labeling reaction. 18 F ion and Cu(OTf) 2 Py 4 After the reaction is completed, the mixture is purified by cation column and dried. The mixture is reacted with HCl solution at 110°C for 10 minutes, neutralized by adding NaOH solution, and hydrolyzed to remove the protective groups of amino and carboxyl groups to obtain a crude product. The crude product is purified by HPLC to obtain a purity of more than 99%. 18 F-BPA can be obtained.

[0066] For the radioactive HPLC spectrum, see Figure 2. 19Mix it with F-BPA, inject it into HPLC, and if a peak appears at the retention time (retention time 11 min ± 1 min) under the same conditions, it is the labeled product. 18 To prove that it is F-BPA, see Figure 3.

[0067] [ka] Using the same preparation method as above, the compound obtained in Example 6 was 18 F-BPA is also produced with a purity of >99%. 18 F-BPA can be obtained.

[0068] [ka] All documents mentioned in this application are incorporated by reference in the same manner as if each document was incorporated by reference in its entirety. It is also to be understood that after reading the above teachings of the present invention, one skilled in the art may make various variations and modifications to the present invention, and that equivalents thereof are also within the scope defined by the claims of this application.

Claims

1. Intermediate I-2, The intermediate I-2 has the structure of formula I-2: 【Chemistry 1】 During the ceremony, B is a boron atom; R １０ and R ２０ are OH or, together with the boron atom to which they are attached, form a boronic acid group (-B(OH) ２ a protecting group for a boronic acid group, which represents a hydrolyzable substituent on the R ３ and R ４ are each independently a hydrogen atom or an amino group (-NH ２ or protecting groups which, together with the nitrogen atom to which they are attached, form an imino group which protects an amino group, R ５ Intermediate I, characterized in that: is a protecting group for a carboxyl group.

2. The hydrolyzable substituent on the boronic acid group is 【Chemistry 2】 、 【Chemistry 3】 、 【Chemistry 4】 、 【Chemistry 5】 、 【Chemistry 6】 、 【Chemistry 7】 or 【Chemistry 8】 2. The intermediate I according to claim 1, wherein

3. The substituent that can be hydrolyzed to the boric acid group is a boric acid ester group, R ３ and R ４ includes an alkoxycarbonyl protecting group, an acyl protecting group, and an alkyl protecting group; R ５ 2. The intermediate I according to claim 1, wherein: is a substituted or unsubstituted C1-C20 alkyl group.

4. In the formula, -BR １０ R ２０ 2. The intermediate I of claim 1, wherein: is a boronic acid pinacol ester group.

5. In the formula, R ３ Or R ４ is, as a protecting group for an amino group, selected from the group consisting of a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a fluorenylmethyloxycarbonyl group, an allyloxycarbonyl group, a trimethylsilylethoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a phthaloyl group, a p-toluenesulfonyl group, a trifluoroacetyl group, an o-nitrobenzenesulfonyl group, a p-nitrobenzenesulfonyl group, a piperoyl group, a benzoyl group, a triphenylmethyl group, a 2,4-dimethoxybenzyl group, a p-methoxybenzyl group, and a benzyl group.

6. In the formula, -NR ３ R ４ teeth 【Chemistry 9】 2. The intermediate I according to claim 1, wherein

7. In the formula, R ５ is a C1 to C10 alkyl group, a phenyl group, or a benzyl group.

8. In the formula, R ５ is a methyl group, an ethyl group, an isopropyl group, a t-butyl group, a diphenylmethyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a 4-benzylpyridine group, a trichloroethyl group, a methylthioethyl group, a p-toluenesulfonylethyl group, a p-nitrobenzylthioxoethyl group, a phenyl group, or a benzyl group.

9. 2. Intermediate I according to claim 1, characterized in that it is selected from the following compounds: 【Chemistry 10】 10. The intermediate I of claim 1, wherein B is 10 atoms of boron.

11. Intermediate I according to claim 3, characterized in that the hydrolyzable substituent on the boronic acid group is a boronic acid pinacol ester group.

12. The intermediate I according to claim 3, wherein R 5 is a t-butyl group.

13. A method for producing 18 F-BPA having the following structure using intermediate I described in claim 1, which contains at least one of an isomer having an L-phenylalanine structure and an isomer having a D-phenylalanine structure: 【Chemistry 11】

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