Intermediates, their preparation methods and methods for preparation of drugs

Abstract

To provide an intermediate of a boron-containing drug for use in treatment of malignant tumors.SOLUTION: An intermediate has the structure illustrated in the formula (1) below, where R1 is -Cl, -Br, -I, -OSO2CF3-, -B(OH)2 or a pinacol boronic ester group illustrated below, R2 is -F, -18F, -Cl, -Br, -I, -SnMe3, -SnBu3, -B(OH)2 or the pinacol boronic ester group, and A is a chiral adjuvant.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to intermediates and methods for their preparation, as well as methods for preparing drugs via the intermediates. [Background technology]

[0002] Malignant tumors are serious diseases that seriously harm human life and health, and currently, methods of treating patients suffering from malignant tumors by radiation therapy are being developed. For example, in the process of boron neutron capture therapy (BNCT), a boron-containing drug is injected into the patient's body to selectively accumulate in tumor cells, and then irradiated with neutron rays, and the boron and neutrons in the tumor cells undergo nuclear fission to generate alpha particles and lithium ions, thereby precisely destroying the tumor cells. When performing BNCT, the distribution location and concentration of the boron-containing drug in the patient's body can be confirmed by positron emission tomography (PET) to ensure that normal cells are not damaged during BNCT and to achieve the desired therapeutic effect. Summary of the Invention [Problem to be solved by the invention]

[0003] In view of the importance of boron-containing drugs for the treatment of malignant tumors, there is a need to develop new and efficient methods for the preparation of boron-containing drugs. [Means for solving the problem]

[0004] The present disclosure has a structure shown in formula (1): [ka] Formula (1) R1 is -Cl, -Br, -I, a trifluorosulfonate group (-OSO2CF3), -B(OH)2, or a pinacol boronic ester group, [ka] ) and R2 is -F, - 18 F, -Cl, -Br, -I, -SnMe3, -SnBu3, -B(OH)2 or pinacol boronic ester group ( [ka] ) where A provides an intermediate which is a chiral auxiliary.

[0005] In some embodiments, A is [ka] where A1 is a C1 to C8 alkyl group, a C7 to C10 aralkyl group or a phenyl group, A2 is a C1 to C8 alkyl group, and A3 is a C1 to C8 alkyl group.

[0006] In some embodiments, A is an imidazolidinone chiral auxiliary or a bislactim ether chiral auxiliary.

[0007] In some embodiments, the intermediate has a structure shown in formula (2), (3), (4), (5), (6), (7), or (8): [ka]

[0008] The present disclosure relates to a method for preparing an intermediate, the method comprising reacting a first reactant with a second reactant in an alkaline environment to obtain a first intermediate, the reaction temperature being −80° C. to 0° C., the first reactant having a structure represented by the following formula (9-1): [ka] R3 is -Cl, -Br, -I or -OSO2CF3 inR4 is -F, -Cl, -Br, -I, -SnMe3, -SnBu3 or -B(OH)2, X is -Br or -I, and the second reactant has a structure shown in the following formula (9-2) or formula (9-3): [ka] The present invention provides a method for preparing an intermediate, in which A1 is a C1-C8 alkyl group, a C7-C10 aralkyl group or a phenyl group, A2 is a C1-C8 alkyl group, and A3 is a C1-C8 alkyl group.

[0009] In some embodiments, the second reactant has a structure shown in formula (10), formula (11), or formula (12): [ka]

[0010] In some embodiments, reacting the first reactant and the second reactant in an alkaline environment includes mixing the first reactant, the second reactant, and an organometallic base, the organometallic base being selected from the group consisting of lithium diisopropylamide (LDA), n-butyllithium (n-butyllithium), and n-butyllithium. m ;n-BuLi), lithium bis(trimethylsilyl)amide (LiHMDS), lithium 2,2,6,6-tetramethylpiperidine, sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, and the like.

[0011] In some embodiments, the first reactant has a structure shown in formula (13) or formula (14): [ka]

[0012] In some embodiments, the method further comprises combining the first reactant, the second reactant, and an aprotic solvent.

[0013] In some embodiments, the aprotic solvent is selected from the group consisting of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), dimethylformamide (DMF), dichloromethane (DCM), and dioxane.

[0014] In some embodiments, the method further comprises reacting the first intermediate with bis(pinacolato)diboron ((Bpin)2) in the presence of a palladium catalyst to obtain a second intermediate.

[0015] In some embodiments, the method further comprises combining the first intermediate, bis(pinacolato)diboron, with an aprotic solvent.

[0016] The present disclosure relates to a method for preparing a drug, the method comprising: reacting the aforementioned intermediate with a fluorinating agent to produce a first compound, wherein in the intermediate, R1 is -Cl, -Br, -I or -OSO2CF3, and R2 is -Cl, -Br, -I, -SnMe3, -SnBu3, -B(OH)2 or [ka] The present invention provides a method for preparing a medicament comprising the steps of:

[0017] In some embodiments, the fluorination reaction of the intermediate with a fluorinating agent comprises reacting the intermediate with K in the presence of a copper catalyst. 18 This involves reacting with F.

[0018] In some embodiments, the method further comprises boronating the first compound with a boronating reagent to produce a second compound.

[0019] In some embodiments, the boronation reaction of the first compound with a boronation reagent comprises reacting the first compound with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0020] In some embodiments, the method further comprises hydrolyzing the second compound.

[0021] It is to be understood that the foregoing general description and the following specific description are merely exemplary and explanatory and are intended to provide further explanation of the present disclosure as desired. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] In this specification, a range expressed as "a certain value to another value" is a general expression form to avoid listing all the values ​​in the range one by one in the specification. Therefore, the description of a certain numerical range encompasses any numerical value in the numerical range and a smaller numerical range defined by any numerical value in the numerical range, and is equivalent to clearly describing the any numerical value and the smaller numerical range in the specification.

[0023] Although the methods disclosed herein are described below using a sequence of operations or steps, the order in which these operations or steps are presented should not be construed as limiting the disclosure. For example, some operations or steps may be performed in different orders and / or simultaneously with other steps. Also, it is not necessary to perform all illustrated operations, steps and / or features to realize embodiments of the disclosure. Also, each operation or step described herein may include multiple sub-steps or actions.

[0024] The present disclosure provides a method for preparing a drug. More specifically, the present disclosure provides a method for preparing a drug, comprising: 18 To provide a method for preparing F-labeled 2-fluoro-4-borono-phenylalanine (FBPA), 18F-labeled FBPA is a boron-containing drug applicable for boron neutron capture therapy (BNCT) and positron emission tomography (PET). 18 Since the half-life of F is shorter than 2 hours, how can it be used as an intermediate in the synthesis of drugs? 18 After labeling F, a simple process 18 It is of considerable importance to prepare F-labeled FBPA. The present disclosure provides an intermediate and a method for its preparation, which can be used to prepare F-labeled FBPA in a simple process. 18 Prepare F-labeled FBPA 18 The synthesis efficiency and yield of F-labeled FBPA can be effectively improved; 18 F-labeled FBPA has excellent specific activity. Various embodiments of the present disclosure will be described below.

[0025] The present disclosure provides an intermediate having the structure shown in formula (1): [ka] R1 is -Cl, -Br, -I, -OSO2CF3 、 -B(OH)2 or [ka] and R2 is -F, - 18 F, -Cl, -Br, -I, -SnMe3, -SnBu3, -B(OH)2 or [ka] and A is a chiral auxiliary. In some embodiments, A is an imidazolidinone chiral auxiliary (also called Seebach's chiral auxiliary) or a bis-lactim ether chiral auxiliary (also called Schollkopf's chiral auxiliary). In some embodiments, A is [ka] where A1 is a C1-C8 alkyl group, a C7-C10 aralkyl group or a phenyl group, A2 is a C1-C8 alkyl group and A3 is a C1-C8 alkyl group. The C1-C8 alkyl group is, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group or an isopentyl group. An "aralkyl group" refers to an alkyl group in which at least one hydrogen atom is replaced by a phenyl group. The C7-C10 aralkyl group is, for example, a C1-C4 alkyl group in which one hydrogen atom is replaced by a phenyl group. In some embodiments, A is [ka] In the present disclosure, chiral auxiliaries having specific structures have been utilized to develop chiral auxiliary precursors for the synthesis of drugs, i.e., intermediates for the preparation of drugs. In some embodiments, the chiral auxiliaries of the present disclosure are 18 It was used to develop F-labeled FBPA asymmetric auxiliary precursor, i.e., to prepare the intermediate of FBPA, which can prepare FBPA by a simple process.

[0026] In some embodiments, the intermediate has a structure shown in formula (2), (3), (4), (5), (6), (7), or (8): [ka] The compound having the structure shown in the above formula (2), formula (3), formula (4), formula (5), formula (6), formula (7) or formula (8) is 18 It may be used as an intermediate for preparing F-labeled FBPA.

[0027] The present disclosure provides a method for preparing an intermediate, comprising reacting a first reactant with a second reactant in an alkaline environment to obtain a first intermediate, and the reaction temperature is −80° C. to 0° C. The reaction temperature is, for example, −80° C., −78° C., −76° C., −74° C., −72° C., −70° C., −60° C., −50° C., −40° C., −30° C., −20° C., −10° C., or 0° C. The first reactant has a structure shown in the following formula (9-1). [ka] R3 is -Cl, -Br, -I or -OSO2CF3 in R4 is -F, -Cl, -Br, -I, -SnMe3, -SnBu3, or -B(OH)2, and X is -Br or -I. The second reactant has a structure shown in formula (9-2) or formula (9-3) below. [ka] A1 is a C1 to C8 alkyl group, a C7 to C10 aralkyl group or a phenyl group, A2 is a C1 to C8 alkyl group, and A3 is a C1 to C8 alkyl group. Therefore, the first intermediate has a structure shown in the following formula (9-4) or formula (9-5). [ka] In some embodiments, the second reactant has a structure shown in formula (10), formula (11), or formula (12): [ka]

[0028] In some embodiments, the first reactant has a structure shown in formula (13) or formula (14): [ka]

[0029] In some embodiments, reacting the first reactant and the second reactant in an alkaline environment comprises combining the first reactant, the second reactant and an organometallic base, wherein the organometallic base is selected from the group consisting of lithium diisopropylamide (LDA), n-butyllithium (n-BuLi), lithium bis(trimethylsilyl)amide (LiHMDS), lithium 2,2,6,6-tetramethylpiperidine, sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, and the like.

[0030] In some embodiments, the method for preparing the intermediate further comprises combining the first reactant, the second reactant and an aprotic solvent, in some embodiments, the aprotic solvent is selected from the group consisting of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), dimethylformamide (DMF), dichloromethane (DCM) and dioxane.

[0031] In some embodiments, the method for preparing the intermediate further comprises reacting the first intermediate with bis(pinacolato)diboron in the presence of a palladium catalyst to obtain a second intermediate. More specifically, R4 in the first intermediate is replaced with a pinacolboronic ester group to form a second intermediate. The palladium catalyst is, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2). In some embodiments, the method for preparing the intermediate further comprises mixing the first intermediate, bis(pinacolato)diboron, with an aprotic solvent. For the aprotic solvent, please refer to the above-mentioned embodiment and will not be described again here. In some embodiments, the temperature at which the first intermediate is reacted with bis(pinacolato)diboron is between 50°C and 120°C, e.g., 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, or 120°C.

[0032] The present disclosure provides a method for preparing a drug, comprising: reacting an intermediate with a fluorinating agent to produce a first compound, wherein in the intermediate, R1 is -Cl, -Br, -I, or -OSO2CF3, and R2 is -Cl, -Br, -I, -SnMe3, -SnBu3, -B(OH)2, or [ka] In some embodiments, the fluorination reagent is K 18 In some embodiments, the fluorination reaction of the intermediate with a fluorinating agent is carried out by reacting the intermediate with a fluorinating agent in the presence of a copper catalyst such as K 18 The method further comprises reacting the first compound with a boronation reagent to produce a second compound. The boronation reagent is, for example, bis(pinacolato)diboron ((Bpin)2). In some embodiments, reacting the first compound with a boronation reagent comprises reacting the first compound with bis(pinacolato)diboron in the presence of a palladium catalyst. In some embodiments, the method further comprises hydrolyzing the second compound.

[0033] The present disclosure includes the following operations: 18 A method for preparing F-labeled 2-fluoro-4-borono-phenylalanine (FBPA) is provided, comprising: subjecting an intermediate to a fluorination reaction to produce a first compound, the first compound having the structure shown in formula (1): [ka] R1 is -Cl, -Br, -I or -OSO2CF3, and R2 is -Cl, -Br, -I, -SnMe3, -SnBu3, -B(OH)2 or [ka] and the first compound has a structure shown in formula (X): [ka] The first compound is subjected to a boronation reaction to produce a second compound having a structure shown in formula (XI) below. [ka] The second compound is hydrolyzed to produce 2-fluoro-4-borono-phenylalanine, having the structure shown in formula (XII) below. [ka]

[0034] In some embodiments, the fluorination reaction of the intermediate comprises reacting the intermediate with K in the presence of a copper catalyst. 18 React with F, and R2 on the aromatic ring becomes 18 In other words, the aromatic ring of the intermediate is 18 The fluorination reaction catalyzed by the copper catalyst is called copper-mediated aromatic ring fluorination reaction. The copper catalyst is, for example, Cu(OTf)2(py)4. In some embodiments, the temperature of the fluorination reaction is 100°C to 120°C. The temperature is, for example, 100°C, 105°C, 110°C, 115°C, or 120°C. In some embodiments, the reaction time of the fluorination reaction is 5 minutes to 60 minutes. 18 F is a pinacol boronic ester group ( [ka] ), followed by other groups such as -Cl, -Br, -I, -SnMe3, -SnBu3, or -B(OH)2. 18 F is accelerated proton to H2 18 Irradiate with O. 18 O(p,n) 18 The reaction produces hydrofluoric acid (H 18 F) and then H 18 F is passed through an ion exchange column and adsorbed into the column, and H2 that is not adsorbed on the column is adsorbed. 18The H in the column can be separated from O by a K2CO3 aqueous solution. 18 By precipitating F, K 18 In some embodiments, during the fluorination reaction, an intermediate, K 18 F and copper catalyst are dissolved in an aprotic solvent such as dimethylformamide (DMF). For the material of the aprotic solvent, please refer to the above embodiment and will not be described again here.

[0035] In some embodiments, the boronation reaction of the first compound includes reacting the first compound with bis(pinacolato)diboron ((Bpin)2) in the presence of a palladium catalyst, whereby R1 on the aromatic ring is replaced with a pinacol boronate ester group. The boronation reaction catalyzed by the above palladium catalyst is called the Miyaura boronation reaction. Bis(pinacolato)diboron is most reactive with -Br, and secondarily reactive with other groups such as -Cl, -I, or -OSO2CF3. The palladium catalyst is, for example, tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), which may be liganded with tricyclohexylphosphine (P(Cy)3). In some embodiments, Pd2(dba)3 may be dissolved in dioxane. The palladium catalyst is, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2). In some embodiments, PdCl2(dppf) may be dissolved in potassium acetate (KOAc). In some embodiments, the temperature of the boronation reaction is 70°C to 120°C. The temperature is, for example, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, or 120°C. In some embodiments, the reaction time of the boronation reaction is 5 minutes to 60 minutes. In some embodiments, during the boronation reaction, the first compound and bis(pinacolato)diboron are dissolved in an aprotic solvent such as dimethylsulfoxide (DMSO) or dioxane. For the material of the aprotic solvent, please refer to the above-mentioned embodiment, and the description will not be repeated here.

[0036] In some embodiments, hydrolyzing the second compound includes reacting the second compound with an acid. The acid can be, for example, hydrogen chloride (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), or a combination thereof. The acid can hydrolyze the pinacol boronic ester group ( [ka] ) can be opened and hydrolyzed to -B(OH)2, and the chiral auxiliary A of the second compound can also be hydrolyzed to an amino acid group. In some embodiments, the temperature of the hydrolysis is 130°C to 170°C. The temperature can be, for example, 130°C, 140°C, 150°C, 160°C, or 170°C. In some embodiments, the reaction time of the hydrolysis is 5 minutes to 60 minutes.

[0037] The features of the present disclosure will be described in more detail below with reference to the following experimental examples. The following experimental examples are described, but the materials used, their amounts and ratios, details of processing, and processing processes may be appropriately changed without going beyond the scope of the present disclosure. Therefore, the present disclosure should not be interpreted as being limited by the following experimental examples.

[0038] Experimental Example 1: Preparation of intermediates having formula (5) and formula (2)

[0039] First, prepare an intermediate having the formula (5), and refer to the following reaction scheme for the preparation process: [ka]

[0040] The preparation process is described in detail below. A compound having the formula (10) (3.0 g) and THF (40 ml), i.e., (S)-tert-butyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate, and THF were added to a 100 ml reaction flask. handThe solution was stirred until the solute was completely dissolved. The temperature of the solution was lowered to -75°C to -70°C with nitrogen gas. The LDA solution (14.0 ml) was added dropwise to the solution, and the temperature was controlled to -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF / hexane. The mixture was stirred for 30 minutes while maintaining the temperature of the solution at -75°C to -70°C. A mixture of 4-bromo-1-(bromomethyl)-2-iodobenzene (4.8 g) and THF (5 ml) was added dropwise to the solution, and the temperature of the solution was controlled to -75°C to -70°C. The solution was allowed to recover to room temperature (room temperature in this specification is about 25°C), and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride solution (50 ml) and dichloromethane (60 ml) to obtain a first organic layer and an aqueous layer, and the aqueous layer was further extracted twice with dichloromethane (30 ml) to obtain a second organic layer. The first organic layer and the second organic layer were combined to obtain an organic layer extract, which was dried over anhydrous sodium sulfate, filtered, and then concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (ethyl ethanoate (EA):heptane=1:5) to obtain the product (4.2 g, 65%). The 1H-nuclear magnetic resonance (NMR) spectrum of the product ( 1 The chemical shifts (δ) (unit: ppm) of H-NMR (400 MHz, CDCl3) were 0.99 (s, 9H), 1.31 (s, 9H), 3.01 (s, 3H), 3.38 (dd, 1H, J = 16.4, 6.8 Hz), 3.52 (dd, 1H, J = 16.4, 3.2 Hz), 4.35 (dd, 1H, J = 6.0, 4.0 Hz), 5.06 (s, 1H), 6.78 (d, 1H, J = 8.4 Hz), 7.35 (dd, 1H, J = 8.4, 2.0 Hz), and 7.97 (d, 1H, J = 1.6 Hz). 1H-NMR spectrum demonstrated that in Experimental Example 1, an intermediate having the above-mentioned formula (5) of the present disclosure can be prepared, and the structure was named (2S,5S)-tert-butyl 5-(4-bromo-2-iodobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate.

[0041] Subsequently, the intermediate having the formula (2) is prepared from the intermediate having the formula (5), and the preparation process is shown in the following reaction scheme. [ka]

[0042] The preparation process is described in detail below. DMSO (5 ml) was added to a 25 ml reaction flask, and argon gas was bubbled for 30 minutes. An intermediate having formula (5) (580 mg), bis(pinacolato)diboron (588 mg), potassium acetate (KOAc) (313 mg), and palladium catalyst Pd(dppf)Cl2 (38.5 mg) were added, and argon gas was continuously bubbled for 10 minutes. The solution was heated with argon gas, and the solution was reacted for 24 hours while controlling the temperature of the solution at 80°C. The temperature of the solution was lowered to room temperature. The solution was extracted with water (15 ml) and dichloromethane (20 ml) to obtain a first organic layer and an aqueous layer, and the aqueous layer was further extracted twice with dichloromethane (15 ml) to obtain a second organic layer. The first organic layer and the second organic layer were combined to obtain an organic layer extract, and the organic layer extract was further extracted with water (15 ml). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (EA:heptane=1:9) to obtain the product (211 mg, 36%). 1 H-NMR spectrum ( 1The chemical shifts (δ) (unit: ppm) of H-NMR (400 MHz, CDCl3) were 0.93 (s, 9H), 1.36 (s, 6H), 1.37 (s, 6H), 1.40 (s, 9H), 2.77 (s, 3H), 3.69 (dd, 1H, J = 15.0, 2.6 Hz), 3.83 (br, 1H), 4.29 (t, 1H, J = 3.6 Hz), 4.77 (s, 1H), 6.82 (d, 1H, J = 8.4 Hz), 7.37 (dd, 1H, J = 8.4, 2.4 Hz), and 7.82 (d, 1H, J = 2.4 Hz). 1 H-NMR spectrum proves that in Experimental Example 1, an intermediate having the above-mentioned formula (2) of the present disclosure can be prepared, and the structure is named (2S,5S)-tert-butyl 5-(4-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate.

[0043] Experimental Example 2: Preparation of intermediates having formula (6) and formula (3)

[0044] First, prepare an intermediate having the formula (6), and refer to the following reaction scheme for the preparation process: [ka]

[0045] The preparation process is described in detail below. A compound having formula (11) (3.9 g) and THF (40 ml), i.e. (S)-benzyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate and THF were added to a 100 ml reaction flask, and the solution was stirred until the solute was completely dissolved. The temperature of the solution was lowered to -75°C to -70°C with nitrogen gas. The LDA solution (16.2 ml) was added dropwise to the solution, and the temperature was controlled to -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF / hexane. The mixture was stirred for 30 minutes while maintaining the temperature of the solution at -75°C to -70°C. A mixture of 4-bromo-1-(bromomethyl)-2-iodobenzene (5.6 g) and THF (5 ml) was added dropwise to the solution, and the temperature of the solution was controlled at -75°C to -70°C. The solution was allowed to return to room temperature, and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride solution (50 ml) and dichloromethane (60 ml) to obtain a first organic layer and an aqueous layer, and the aqueous layer was further extracted twice with dichloromethane (30 ml) to obtain a second organic layer. The first organic layer and the second organic layer were combined to obtain an organic layer extract, and the organic layer extract was dried over anhydrous sodium sulfate, filtered, and then concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (EA:heptane=1:5) to obtain the product (5.5 g, 70%). The product 1 H-NMR spectrum ( 1 The chemical shifts (δ) (unit: ppm) of H-NMR (400 MHz, CDCl3) were 0.98 (s, 9H), 3.00 (s, 3H), 3.32 (dd, 1H, J = 15.6, 6.4 Hz), 3.53 (d, 1H, J = 15.2 Hz), 4.40 (t, 1H, J = 5.2 Hz), 4.89 (d, 1H, J = 12.0 Hz), 5.09 (s, 1H), 5.15 (d, 1H, J = 12.0 Hz), 6.82 (d, 1H, J = 8.4 Hz), 7.21-7.32 (m, 6H), and 7.90 (s, 1H). 1H-NMR spectrum demonstrated that in Experimental Example 2, an intermediate having the above-mentioned formula (6) of the present disclosure can be prepared, and the structure was named (2S,5S)-benzyl 5-(4-bromo-2-iodobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate.

[0046] Subsequently, the intermediate having the formula (3) is prepared from the intermediate having the formula (6), and the preparation process is shown in the following reaction scheme. [ka]

[0047] The preparation process is described in detail below. DMSO (5 ml) was added to a 25 ml reaction flask, and argon gas was bubbled for 30 minutes. An intermediate having formula (6) (500 mg), bis(pinacolato)diboron (477 mg), potassium acetate (254 mg), and palladium catalyst Pd(dppf)Cl2 (31.3 mg) were added, and argon gas was continuously bubbled for 10 minutes. The solution was heated with argon gas, and the solution was reacted for 22 hours while controlling the temperature of the solution at 80°C. The temperature of the solution was lowered to room temperature. The solution was extracted with water (15 ml) and dichloromethane (20 ml) to obtain a first organic layer and an aqueous layer, and the aqueous layer was further extracted twice with dichloromethane (15 ml) to obtain a second organic layer. The first organic layer and the second organic layer were combined to obtain an organic layer extract, and the organic layer extract was further extracted with water (15 ml). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (EA:heptane=1:7) to obtain the product (246 mg, 49%). 1 H-NMR spectrum ( 1The chemical shifts (δ) (unit: ppm) of H-NMR (400 MHz, CDCl3) were 0.88 (s, 9H), 1.37 (s, 12H), 2.78 (s, 3H), 3.64 (d, 1H, J = 12.8 Hz), 3.88 (br, 1H), 4.35 (t, 1H, J = 3.2 Hz), 4.69 (s, 1H), 4.93 (d, 1H, J = 11.6 Hz), 5.20 (d, 1H, J = 12.0 Hz), 6.72 (d, 1H, J = 8.0 Hz), 7.25-7.36 (m, 6H), and 7.79 (d, 1H, J = 2.4 Hz). 1 H-NMR spectrum proves that in Experimental Example 2, an intermediate having the above-mentioned formula (3) of the present disclosure can be prepared, and the structure is named (2S,5S)-benzyl 5-(4-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate.

[0048] Experimental Example 3: Preparation of intermediate having formula (7)

[0049] For the preparation of the intermediate having formula (7), see the following reaction scheme: [ka]

[0050] The preparation process is described in detail below. A 100 ml reaction flask was charged with a compound having the formula (10) (200 mg) and THF (5 ml), i.e. (S)-tert-Butyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylateand THF were added, and the solution was stirred until the solute was completely dissolved. The temperature of the solution was lowered to -75°C to -70°C with nitrogen gas. The LDA solution (0.94 ml) was added dropwise to the solution, and the temperature was controlled to -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF / hexane. The mixture was stirred for 30 minutes while maintaining the temperature of the solution at -75°C to -70°C. A mixture of 4-bromo-1-(bromomethyl)-2-fluorobenzene (209 mg) and THF (2 ml) was added dropwise to the solution, and the temperature of the solution was controlled to -75°C to -70°C. The solution was allowed to return to room temperature, and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride solution (10 ml) and dichloromethane (15 ml) to obtain a first organic layer and an aqueous layer, and the aqueous layer was further extracted twice with dichloromethane (10 ml) to obtain a second organic layer. The first organic layer and the second organic layer were combined to obtain an organic layer extract, which was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (EA:heptane=1:5) to obtain the product (105 mg, 30%). 1 H-NMR spectrum ( 1 The chemical shifts (δ) (unit: ppm) of H-NMR (400 MHz, CDCl3) were 0.95 (s, 9H), 1.41 (s, 9H), 2.87 (s, 3H), 3.31 (dd, 1H, J = 15.0, 2.2 Hz), 3.54 (br, 1H), 4.31 (s, 1H), 4.83 (s, 1H), 6.96 (t, 1H, J = 8.2 Hz), and 7.13-7.17 (m, 2H). 1H-NMR spectrum proves that the intermediate having the above-mentioned formula (7) of the present disclosure can be prepared in Experimental Example 3, and its structure is named (2S,5S)-tert-butyl 5-(4-bromo-2-fluorobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate. The intermediate having the formula (7) can further react with bis(pinacolato)diboron to replace the F group with a pinacolboronic acid ester group, and the product can be used to prepare FBPA, and the reaction process can refer to Experimental Example 1 or Experimental Example 2.

[0051] Experimental Example 4: Preparation of intermediate having formula (8)

[0052] For the preparation of the intermediate having formula (8), see the following reaction scheme: [ka] The preparation process is described in detail below. A compound having formula (11) (200 mg) and THF (5 ml), i.e. (S)-benzyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate and THF were added to a 100 ml reaction flask, and the solution was stirred until the solute was completely dissolved. The temperature of the solution was lowered to -75°C to -70°C with nitrogen gas. An LDA solution (0.83 ml) was added dropwise to the solution, and the temperature was controlled to -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF / hexane. The mixture was stirred for 30 minutes while maintaining the temperature of the solution at -75°C to -70°C. A mixture of 4-bromo-1-(bromomethyl)-2-fluorobenzene (185 mg) and THF (2 ml) was added dropwise to the solution, and the temperature of the solution was controlled at -75°C to -70°C. The solution was allowed to return to room temperature, and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride solution (10 ml) and dichloromethane (15 ml) to obtain a first organic layer and an aqueous layer, and the aqueous layer was further extracted twice with dichloromethane (10 ml) to obtain a second organic layer. The first organic layer and the second organic layer were combined to obtain an organic layer extract, and the organic layer extract was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a concentrate. The concentrate was purified by flash column chromatography (EA:heptane=1:4) to obtain the product (77 mg, 23%). The product 1 H-NMR spectrum ( 1 The chemical shifts (δ) (unit: ppm) of H-NMR (400 MHz, CDCl3) were 0.91 (s, 9H), 2.84 (s, 3H), 3.19 (d, 1H, J = 14.0 Hz), 3.65 (dd, 1H, J = 14.0, 3.2 Hz), 4.38 (s, 1H), 4.81 (s, 1H), 4.96 (d, 1H, J = 12.0 Hz), 5.26 (d, 1H, J = 12.0 Hz), 6.96 (t, 1H, J = 8.0 Hz), 7.08-7.14 (m, 2H), and 7.35-7.39 (m, 5H). 1H-NMR spectrum proves that the intermediate having the above-mentioned formula (8) of the present disclosure can be prepared in Experimental Example 4, and its structure is named (2S,5S)-benzyl 5-(4-bromo-2-fluorobenzyl)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate. The intermediate having the formula (8) can further react with bis(pinacolato)diboron to replace the F group with a pinacolboronic acid ester group, and the product can be used to prepare FBPA, and the reaction process can refer to Experimental Example 1 or Experimental Example 2.

[0053] Experimental Example 5: Using an intermediate having the structure of formula (2) 18 Preparation of F-labeled FBPA

[0054] The preparation process is shown in the following reaction scheme: [ka]

[0055] The preparation process is described in detail below. The intermediate having the structure of formula (2) is used as a starting material, and is fluorinated in the presence of a copper catalyst Cu(OTf)2(py)4 to produce the intermediate K. 18 By reacting with F, the pinacolboronic ester group on the aromatic ring can be 18 In the fluorination reaction, the solvent was dimethylformamide (DMF), and K 222is an aminopolyether, the reaction temperature was 110°C, and the reaction time was 20 minutes. A boronation reaction was then carried out, in which the fluorinated intermediate was reacted with bis(pinacolato)diboron ((Bpin)2) in the presence of a palladium catalyst Pd2(dba)3 to replace -Br on the aromatic ring with a pinacol boronate ester group. The palladium catalyst Pd2(dba)3 has P(Cy)3 as a ligand. In the boronation reaction, Pd2(dba)3 and (Bpin)2 are soluble in dioxane, the solvent may be potassium acetate (KOAc) and water, the reaction temperature was 110°C, and the reaction time was 15 minutes. A hydrolysis reaction was then carried out, in which the intermediate was reacted with hydrogen bromide (HBr), which converted the pinacol boronate ester group ( [ka] ) can be hydrolyzed to -B(OH)2, and the chiral auxiliary can be hydrolyzed to an amino acid group. In the hydrolysis reaction, the reaction temperature was 150°C, and the reaction time was 20 minutes.

[0056] Experimental Example 6: Using an intermediate having the structure of formula (3) 18 Preparation of F-labeled FBPA

[0057] The preparation process is shown in the following reaction scheme: [ka]

[0058] The preparation process is described in detail below. Starting with an intermediate having the structure of formula (3), 18 Prepare F-labeled FBPA. For the reaction conditions of Experimental Example 6, please refer to Experimental Example 5 above. The difference between Experimental Example 5 and Experimental Example 6 is that the starting materials are different, so the reaction process of Experimental Example 6 is not repeated here.

[0059] In summary, the present disclosure provides a method for preparing a drug, an intermediate for synthesizing the drug, and a method for preparing the intermediate. 18The present disclosure relates to a method for preparing F-labeled FBPA, an intermediate for synthesizing FBPA, and a method for preparing the intermediate. The method for preparing FBPA in the present disclosure has a simple process, can effectively improve the synthesis efficiency and yield of FBPA, and can make FBPA have good specific activity.

[0060] Although the present disclosure has been described in considerable detail with reference to certain embodiments, other embodiments are possible, and therefore, the spirit and scope of the appended claims should not be limited to the description of the embodiments contained herein.

[0061] It will be apparent to those skilled in the art that various modifications and variations can be made to the structure of the present disclosure without departing from the scope or spirit of the disclosure. In view of the foregoing, it is intended that the present disclosure covers modifications and variations of the present disclosure that fall within the scope of the appended claims.

Claims

1. It has a structure shown in the following formula (1): 【Chemistry 1】 R １ is -Br, -I, -OSO ２ CF ３ , -B(OH) ２ or 【Chemistry 2】 and R ２ , -F, - １８ F, -Cl, -Br, -I, -SnMe ３ , -SnBu ３ , -B(OH) ２ or 【Chemistry 3】 and A is a chiral auxiliary, i.e. 【Chemistry 4】 A 1 is a C1-C8 alkyl group, a C7-C10 aralkyl group, or a phenyl group, and A 2 is a C1-C8 alkyl group, or R 1 is -Cl, -I, -OSO 2 CF 3 , -B(OH) 2 or 【Chemistry 5】 and R 2 is —F, — 18 F, —Cl, —Br, —I, —SnMe 3 , —SnBu 3 , —B(OH) 2 or 【Chemistry 6】 and A is a chiral auxiliary, i.e. 【Chemistry 7】 and A 3 is a C1-C8 alkyl group.

2. The intermediate according to claim 1, wherein the intermediate has a structure represented by the following formula (2), formula (3), formula (4), formula (5), formula (6), formula (7), or formula (8). 【Chemistry 8】

3. A method for preparing an intermediate, comprising reacting a first reactant having a structure as shown in formula (9-1) with a second reactant having a structure as shown in formula (9-2) or (9-3) in an alkaline environment to obtain a first intermediate having a structure as shown in formula (9-4) or (9-5), wherein the reaction temperature is −80° C. to 0° C.; The first reactant has a structure shown in the following formula (9-1): 【Chemistry 9】 R ３ is -Cl, -Br, -I or -OSO ２ CF3, R ４ -F, -Cl, -Br, -I, -SnMe ３ , -SnBu ３ Or -B(OH) ２ and X is -Br or -I; The second reactant has a structure shown in the following formula (9-2) or formula (9-3): 【Chemistry 10】 A １ is a C1-C8 alkyl group, a C7-C10 aralkyl group, or a phenyl group; A ２ is a C1 to C8 alkyl group; A ３ is a C1 to C8 alkyl group, The first intermediate has a structure shown in the following formula (9-4) or (formula 9-5): 【Chemistry 11】 reacting the first intermediate with bis(pinacolato)diboron in the presence of a palladium catalyst to obtain a second intermediate; The second intermediate is 【Chemistry 12】 A process for the preparation of an intermediate

4. The method of claim 3 , wherein the second reactant has a structure shown in formula (10), formula (11), or formula (12): 【Chemistry 13】

5. 4. The method of claim 3, wherein reacting the first reactant and the second reactant in an alkaline environment comprises mixing the first reactant, the second reactant and an organometallic base, wherein the organometallic base is selected from the group consisting of lithium diisopropylamide, n-butyllithium, lithium bis(trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidine, sodium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide and the like.

6. The method of claim 3 , wherein the first reactant has a structure shown in formula (13) or formula (14): 【Chemistry 14】

7. 4. The method of claim 3, further comprising combining the first reactant, the second reactant and an aprotic solvent.

8. The method of claim 7, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, dichloromethane and dioxane.

9. 4. The method of claim 3, further comprising combining said first intermediate, said bis(pinacolato)diboron, with an aprotic solvent.

10. 11. A method for preparing a drug, comprising: subjecting the intermediate of claim 1 to a fluorination reaction with a fluorinating agent to produce a first compound having the following formula (X): 【Chemistry 15】 In the intermediate, R １ is -Cl, -Br, -I or -OSO ２ CF ３ and R ２ is -Cl, -Br, -I, -SnMe ３ , -SnBu ３ , -B(OH) ２ or 【Chemistry 16】 A method for preparing a drug comprising the steps of:

11. The fluorination reaction of the intermediate according to claim 1 with the fluorinating agent comprises reacting the intermediate according to claim 1 with K in the presence of a copper catalyst. １８ 11. The method of claim 10 comprising reacting with F.

12. The first compound is subjected to a boronation reaction with a boronation reagent to obtain a second compound having the following formula (XI): 【Chemistry 17】 The method of claim 10 , further comprising generating:

13. 13. The method of claim 12, wherein the boronation reaction of the first compound with the boronation reagent comprises reacting the first compound with bis(pinacolato)diboron in the presence of a palladium catalyst.

14. 13. The method of claim 12, further comprising hydrolyzing the second compound.

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