TW202330475A - Intermediate, preparing method thereof, and method of preparing drug - Google Patents

Abstract

An intermediate is provided and has the structure shown in formula (1) as follows:, in which R1 is -Cl, -Br, -I, -OSO2CF3, -B(OH)2, or, R2 is -F, -18F, -Cl, -Br, -I, -SnMe3, -SnBu3, -B(OH)2, or, and A is a chiral auxiliary.

Description

Intermediates, methods for their preparation and methods for the preparation of medicaments

The present disclosure relates to intermediates and methods for their preparation, as well as methods for the preparation of medicaments from the intermediates.

Malignant tumors are major diseases that seriously endanger human life and health. At present, a method of treating patients suffering from malignant tumors by radiotherapy has been developed. For example, the process of Boron Neutron Capture Therapy (BNCT) is as follows: Boron-containing drugs are injected into the patient's body, and the boron-containing drugs will selectively accumulate in tumor cells, and then irradiated with neutron beams , boron and neutrons in tumor cells undergo nuclear fission to generate alpha particles and lithium ions, thereby precisely destroying tumor cells. During BNCT, the distribution position and concentration of boron-containing drugs in the patient can be confirmed by Positron Emission Tomography (PET), so as to ensure that normal cells will not be damaged and the expected treatment can be achieved during BNCT Effect.

In view of the importance of boron-containing drugs for the treatment of malignant tumors, novel and efficient methods for preparing boron-containing drugs need to be developed.

The present disclosure provides an intermediate having a structure as shown in the following formula (1): Formula (1), wherein R ₁ is -Cl, -Br, -I, trifluorosulfonate (-OSO ₂ CF ₃ ), -B(OH) ₂ or pinacol boronic ester group, ), R ₂ is -F, - ¹⁸ F, -Cl, -Br, -I, -SnMe ₃ , -SnBu ₃ , -B(OH) ₂ or pinacol borate group ( ), A is a chiral auxiliary.

In some embodiments, A is or , wherein _A1 is C1-C8 alkyl, C7-C10 aralkyl or phenyl, _A2 is C1-C8 alkyl, and _A3 is C1-C8 alkyl.

In some embodiments, A is an imidazolinone chiral auxiliary or a bis-lactimide ether chiral auxiliary.

In some embodiments, the intermediate has a structure as shown in the following formula (2), formula (3), formula (4), formula (5), formula (6), formula (7) or formula (8): Formula (2), formula (3), formula (4), Formula (5), Formula (6), Equation (7), or Formula (8).

The present disclosure provides a method for preparing an intermediate, which includes the following operations. reacting the first reactant with the second reactant under a basic environment to obtain the first intermediate, wherein the reaction temperature is from -80°C to 0°C. The first reactant has a structure as shown in the following formula (9-1): Formula (9-1), R ₃ is -Cl, -Br, -I or -OSO ₂ CF ₃ , R ₄ is -F, -Cl, -Br, -I, -SnMe ₃ , -SnBu ₃ or -B (OH) ₂ , X is -Br or -I. The second reactant has a structure as shown in the following formula (9-2) or formula (9-3): Formula (9-2), Formula (9-3), wherein A ₁ is a C1-C8 alkyl group, a C7-C10 aralkyl group or a phenyl group, A ₂ is a C1-C8 alkyl group, and A ₃ is a C1-C8 alkyl group.

In some embodiments, the second reactant has a structure as shown in the following formula (10), formula (11) or formula (12): Formula (10), Equation (11) or Formula (12).

In some embodiments, reacting the first reactant with the second reactant under an alkaline environment comprises: mixing the first reactant, the second reactant, and an organometallic base selected from the group consisting of diiso Lithium diisopropylamide (LDA), n-butyllithium (butyllithiu, n-BuLi), Lithium bis(trimethylsilyl)amide, LiHMDS), 2,2,6, Lithium 6-tetramethylpiperidine, sodium methoxide, lithium tertiary butoxide, sodium tertiary butoxide, potassium tertiary butoxide, sodium ethoxide and groups thereof.

In some embodiments, the first reactant has a structure as shown in the following formula (13) or formula (14): Equation (13) or Formula (14).

In some embodiments, the method further includes mixing the first reactant, the second reactant, and the aprotic solvent.

In some embodiments, the aprotic solvent is selected from tetrahydrofuran (Tetrahydrofuran, THF), 2-methyltetrahydrofuran (2-MeTHF), dimethylformamide (Dimethylformamide, DMF), dichloromethane (Dichloromethane, DCM) and Dioxane (Dioxane) group.

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

In some embodiments, the method further includes: mixing the first intermediate, bis-pinacol borate, and an aprotic solvent.

The present disclosure provides a method for preparing medicine, including the following operations. The aforementioned intermediate is fluorinated with a fluorinating reagent to generate the first compound, wherein 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 .

In some embodiments, fluorinating the intermediate with a fluorinating agent comprises: reacting the intermediate with K ¹⁸ F in the presence of a copper catalyst.

In some embodiments, the method further includes: performing a borylation reaction of the first compound with a borylation reagent to generate a second compound.

In some embodiments, performing borylation reaction of the first compound with a borylation reagent comprises: reacting the first compound with bis-pinacol borate in the presence of a palladium catalyst.

In some embodiments, the method further includes: hydrolyzing the second compound.

It is to be understood that both the foregoing general description and the following specific description are exemplary and explanatory only and are intended to provide further explanation of the disclosure as claimed.

Herein, a range indicated by "one value to another value" is a general representation which avoids enumerating all values in the range in the specification. Therefore, the description of a specific numerical range covers any numerical value in the numerical range and the smaller numerical range bounded by any numerical value in the numerical range, as if the arbitrary numerical value and the smaller numerical value are expressly written in the specification. same range.

Although a series of operations or steps are used to illustrate the methods disclosed herein, the order of these operations or steps should not be construed as a limitation of the present disclosure. For example, certain operations or steps may be performed in a different order and/or concurrently with other steps. In addition, not all illustrated operations, steps and/or features must be performed to implement an implementation of the present disclosure. Furthermore, each operation or step described herein may contain several sub-steps or actions.

The present disclosure provides a preparation method of a medicine. In more detail, the present disclosure provides a preparation method of ¹⁸ F-labeled 2-fluoro-4-dihydroxyboryl-phenylalanine (2-fluoro-4-borono-phenylalanine, FBPA), ¹⁸ F-labeled FBPA is a boron-containing drug that can be used in boron neutron capture therapy (BNCT) and positron tomography (PET). Since the half-life of ¹⁸ F is shorter than two hours, it is very important how to prepare ¹⁸ F-labeled FBPA in a simple process after labeling ¹⁸ F on the intermediate of the synthetic drug. The present disclosure provides an intermediate and its preparation method, and ¹⁸ F-labeled FBPA can be prepared from this intermediate in a simple process, thereby effectively improving the efficiency and yield of synthesizing ¹⁸ F-labeled FBPA, and ¹⁸ F-labeled FBPA Has good specific activity. Various embodiments of the present disclosure will be described respectively below.

The present disclosure provides an intermediate having a structure as shown in the following formula (1): Formula (1), wherein R ₁ is -Cl, -Br, -I, -OSO ₂ CF ₃ , -B(OH) ₂ or , R ₂ is -F, - ¹⁸ F, -Cl, -Br, -I, -SnMe ₃ , -SnBu ₃ , -B(OH) ₂ or , A is a chiral auxiliary. In some embodiments, A is an imidazolidinone chiral auxiliary (also known as Seebach's chiral auxiliary) or a bis-lactim ether chiral auxiliary (Also known as Schöllkopf's chiral auxiliary (Schöllkopf's chiral auxiliary)). In some embodiments, A is or , wherein _A1 is C1-C8 alkyl, C7-C10 aralkyl or phenyl, _A2 is C1-C8 alkyl, and _A3 is C1-C8 alkyl. The C1-C8 alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, second-butyl, isobutyl, tert-butyl, n-pentyl or isopentyl. "Aralkyl" 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 substituted by a phenyl group. In some embodiments, A is , or . The present disclosure utilizes chiral auxiliaries with specific structures to develop anti-palm auxiliary precursors for the synthesis of drugs, that is, intermediates for the preparation of drugs. In some embodiments, the chiral auxiliaries of the present disclosure can be used to develop ¹⁸ F-labeled FBPA on-ancillary precursors, ie, intermediates for the preparation of FBPA, thereby preparing FBPA in a facile procedure.

In some embodiments, the intermediate has a structure as shown in the following formula (2), formula (3), formula (4), formula (5), formula (6), formula (7) or formula (8): Formula (2), Formula (3), formula (4), Formula (5), Formula (6), Equation (7), or Formula (8). The above-mentioned structures represented by formula (2), formula (3), formula (4), formula (5), formula (6), formula (7) or formula (8) can be used as intermediates for the preparation of ¹⁸ F-labeled FBPA body.

The present disclosure provides a method for preparing an intermediate, which includes the following operations. reacting the first reactant with the second reactant under a basic environment to obtain the first intermediate, wherein the reaction temperature is from -80°C to 0°C. The reaction temperature is, for example, -80, -78, -76, -74, -72, -70, -60, -50, -40, -30, -20, -10 or 0°C. The first reactant has a structure as shown in the following formula (9-1): Formula (9-1), R ₃ is -Cl, -Br, -I or -OSO ₂ CF ₃ , R ₄ is -F, -Cl, -Br, -I, -SnMe ₃ , -SnBu ₃ or -B (OH) ₂ , X is -Br or -I. The second reactant has a structure as shown in the following formula (9-2) or formula (9-3): Formula (9-2), Formula (9-3), wherein A ₁ is a C1-C8 alkyl group, a C7-C10 aralkyl group or a phenyl group, A ₂ is a C1-C8 alkyl group, and A ₃ is a C1-C8 alkyl group. Therefore, the first intermediate has the structure shown in the following formula (9-4) or formula (9-5): Formula (9-4), Formula (9-5). In some embodiments, the second reactant has a structure as shown in the following formula (10), formula (11) or formula (12): formula (10), Equation (11) or Formula (12).

In some embodiments, the first reactant has a structure as shown in the following formula (13) or formula (14): Equation (13) or Formula (14).

In some embodiments, reacting the first reactant with the second reactant under an alkaline environment comprises: mixing the first reactant, the second reactant, and an organometallic base selected from the group consisting of diiso Lithium propylamide (LDA), n-butyllithium (n-BuLi), lithium bis(trimethylsilyl)amide (LiHMDS), lithium 2,2,6,6-tetramethylpiperidine, sodium methoxide, Lithium tertiary butoxide, sodium tertiary butoxide, potassium tertiary butoxide and sodium ethoxide and groups thereof.

In some embodiments, the method of preparing the intermediate further includes mixing the first reactant, the second reactant and an aprotic solvent. In some embodiments, the aprotic solvent is selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), dimethylformamide (DMF), dichloromethane (DCM) and dioxane (Dioxane) group.

In some embodiments, the method for preparing the intermediate further includes reacting the first intermediate with bis-pinacol borate in the presence of a palladium catalyst to obtain the second intermediate. In more detail, _R4 in the first intermediate will be substituted with a pinacol borate group to form the second intermediate. The palladium catalyst is, for example, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl ₂ ). In some embodiments, the method for preparing the intermediate further includes mixing the first intermediate, bis-pinacol borate, and an aprotic solvent. For the aprotic solvent, please refer to the aforementioned embodiments, and details will not be repeated here. In some embodiments, the temperature at which the first intermediate is reacted with bis-linked pinacol borate is from 50°C to 120°C, such as 50, 55, 60, 65, 70, 75, 80, 85, 90 , 95, 100, 105, 110, 115 or 120°C.

The present disclosure provides a method for preparing a drug, comprising: fluorinating an intermediate with a fluorinating reagent to generate a first compound, wherein in the intermediate, _R is -Cl, -Br, -I or -OSO ₂ CF ₃ , R ₂ is -Cl, -Br, -I, -SnMe ₃ , -SnBu ₃ , -B(OH) ₂ or . In some embodiments, the fluorinating agent is a metal fluoride, such as K ¹⁸ F. In some embodiments, the fluorination reaction of the intermediate with a fluorinating reagent comprises: reacting the intermediate with K ¹⁸ F in the presence of a copper catalyst. The copper catalyst is, for example, Cu(OTf) ₂ (py) ₄ . In some embodiments, the method further includes subjecting the first compound to a borylation reagent to form a second compound. The borylation reagent is, for example, bispinacol borate ((Bpin) ₂ ). In some embodiments, performing borylation reaction of the first compound with a borylation reagent comprises: reacting the first compound with bis-pinacol borate in the presence of a palladium catalyst. In some embodiments, the method further includes hydrolyzing the second compound.

The present disclosure provides a method for preparing ¹⁸ F-labeled 2-fluoro-4-dihydroxyboryl-phenylalanine (FBPA), comprising the following operations. The intermediate is subjected to a fluorination reaction to generate the first compound, wherein the intermediate has a structure as shown in the following formula (1): Formula (1), R ₁ is -Cl, -Br, -I or -OSO ₂ CF ₃ , R ₂ is -Cl, -Br, -I, -SnMe ₃ , -SnBu ₃ , -B(OH) ₂ or , the first compound has the structure shown in the following formula (X): Formula (X). Make the first compound carry out borylation reaction, generate the second compound, the second compound has the structure shown in following formula (XI): Formula (XI). Hydrolysis of the second compound produces 2-fluoro-4-dihydroxyboryl-phenylalanine, which has the structure shown in the following formula (XII): Formula (XII).

In some embodiments, subjecting the intermediate to fluorination comprises: reacting the intermediate with K ¹⁸ F in the presence of a copper catalyst so that R ₂ on the aromatic ring is replaced by ¹⁸ F, in other words, the aromatic ring of the intermediate Fluorinated by ¹⁸ F. The above-mentioned fluorination reaction catalyzed by 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 from 100°C to 120°C. The temperature is for example 100, 105, 110, 115 or 120°C. In some embodiments, the reaction time of the fluorination reaction is 5 minutes to 60 minutes. K ¹⁸ F and pinacol borate group ( ) has the best reactivity, followed by other groups such as -Cl, -Br, -I, -SnMe ₃ , -SnBu ₃ or -B(OH) ₂ . In some embodiments, K ¹⁸ F can be obtained by the following operation: irradiating H ₂ ¹⁸ O with accelerated protons, using ¹⁸ O(p,n) ¹⁸ F to synthesize hydrofluoric acid (H ¹⁸ F), and then converting H ¹⁸ F It is adsorbed in the column through an ion exchange column to separate from H ₂ ¹⁸ O that is not adsorbed in the column. Precipitate H ¹⁸ F in the column with K ₂ CO ₃ aqueous solution to obtain K ¹⁸ F. In some embodiments, during the fluorination reaction, the 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 foregoing embodiments, and details are not repeated here.

In some embodiments, the borylation reaction of the first compound comprises: reacting the first compound with bis-pinacol borate ((Bpin) ₂ ) in the presence of a palladium catalyst, so that the R on the aromatic ring ₁ is substituted with a pinacol borate group. The above-mentioned borylation reaction catalyzed by palladium catalyst is called Miyaura borylation reaction. The bilinked pinacol borate has the best reactivity with -Br, followed by other groups such as -Cl, -I or -OSO ₂ CF ₃ . The palladium catalyst is, for example, tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ), which can use tricyclohexylphosphine (P(Cy) ₃ ) as a ligand. In some embodiments, Pd ₂ (dba) ₃ can be dissolved in dioxane. The palladium catalyst is, for example, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl ₂ ). In some embodiments, PdCl ₂ (dppf) can be dissolved in Potassium acetate (KOAc). In some embodiments, the temperature of the borylation reaction is from 70°C to 120°C. The temperature is for example 70, 75, 80, 85, 90, 95, 100, 105, 110, 115 or 120°C. In some embodiments, the reaction time of the borylation reaction is 5 minutes to 60 minutes. In some embodiments, when carrying out the borylation reaction, the first compound and bis-pinacol borate are dissolved in an aprotic solvent, such as dimethylsulfoxide (DMSO) or dioxane (Dioxane). For the material of the aprotic solvent, please refer to the foregoing embodiments, and details are not repeated here.

In some embodiments, hydrolyzing the second compound includes reacting the second compound with an acid. The acid is, for example, hydrogen chloride (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), or combinations thereof. The acid can open the pinacol borate group of the second compound ( ) to hydrolyze it into -B(OH) ₂ , and the acid can also hydrolyze the chiral auxiliary A of the second compound into an amino acid group. In some embodiments, the temperature of hydrolysis is from 130°C to 170°C. The temperature is for example 130, 140, 150, 160 or 170°C. In some embodiments, the reaction time for hydrolysis is 5 minutes to 60 minutes.

Hereinafter, features of the present disclosure will be described more specifically with reference to experimental examples. Although the following experimental examples are described, the materials used, their amounts and ratios, processing details, processing flow, and the like can be appropriately changed without departing from the scope of the present disclosure. Therefore, the present disclosure should not be limitedly interpreted by the experimental examples described below.

Experimental example 1: preparation has the intermediate of formula (5) and formula (2)

First, prepare the intermediate with formula (5), please refer to the following reaction formula for the preparation process.

The preparation process will be described in detail below. Add the compound (3.0 g) and THF (40 ml) having the formula (10) into a 100 ml reaction flask, namely (S)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1- tert-butyl carboxylate ((S)-tert-butyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate) and THF, at °C, stir the solution until the solute is completely dissolved. Lower the solution temperature to -75 °C to -70 °C under nitrogen. LDA solution (14.0 ml) was added dropwise to the solution, and the temperature was controlled at -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF/hexane. Keep the solution temperature at -75°C to -70°C and stir the mixture for 30 min. A mixture of 4-bromo-1-(bromomethyl)-2-iodobenzene (4-bromo-1-(bromomethyl)-2-iodobenzene) (4.8 g) and THF (5 ml) was added dropwise to the solution, Control the solution temperature at -75°C to -70°C. The solution was warmed to room temperature (room temperature here is about 25° C.), and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride (50 ml) and dichloromethane (60 ml) to obtain the first organic layer and the aqueous layer, and the aqueous layer was extracted twice with dichloromethane (30 ml) to obtain the second organic layer . The first organic layer and the second organic layer were combined into 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 acetate (EA):heptane=1:5) to obtain the product (4.2 g, 65%). The chemical shift (δ) (unit: ppm) of the product's nuclear magnetic resonance (NMR) hydrogen spectrum ( ¹ H-NMR (400 MHz, CDCl ₃ )) is 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), 7.97 (d, 1H, J = 1.6 Hz). It can be proved from the NMR hydrogen spectrum that Experimental Example 1 can prepare the intermediate of formula (5) in the foregoing disclosure, and its structure is named as (2S, 5S)-tert-butyl 5-(4-bromo-2-iodobenzyl)- 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate.

Next, the intermediate of formula (2) is prepared from the intermediate of formula (5). Please refer to the following reaction formula for the preparation process.

The preparation process will be described in detail below. DMSO (5 ml) was added to a 25 ml reaction vial and bubbled with argon for 30 minutes. The intermediate of formula (5) (580 mg), bis-pinacol borate (588 mg), potassium acetate (KOAc) (313 mg) and palladium catalyst Pd(dppf) _Cl (38.5 mg) were added, Continue bubbling with argon for 10 minutes. The solution was heated under argon, and the temperature of the solution was controlled to be 80° C. to allow the solution to react for 24 hours. 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 extracted twice with dichloromethane (15 ml) to obtain a second organic layer. The first organic layer and the second organic layer were combined into an organic layer extract, and the organic layer extract was extracted with water (15 ml). 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=1:9) to obtain the product (211 mg, 36%). The chemical shifts (δ) (unit: ppm) of the NMR spectrum ( ¹ H-NMR (400 MHz, CDCl ₃ )) of the product are 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), 7.82 (d, 1H, J = 2.4 Hz). It can be proved by NMR hydrogen spectrum that Experimental Example 1 can prepare the intermediate of formula (2) in the foregoing disclosure, and its structure is named as (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.

Experimental example 2: preparation has the intermediate of formula (6) and formula (3)

First, prepare the intermediate with formula (6), please refer to the following reaction formula for the preparation process.

The preparation process will be described in detail below. Add the compound (3.9 g) and THF (40 ml) having the formula (11) into a 100 ml reaction flask, that is, (S)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1- Benzyl formate 1-carboxylate ((S)-benzyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate) and THF, the solution was stirred until the solute was completely dissolved. Lower the solution temperature to -75 °C to -70 °C under nitrogen. LDA solution (16.2 ml) was added dropwise to the solution, and the temperature was controlled at -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF/hexane. Keep the solution temperature at -75°C to -70°C and stir the mixture for 30 min. 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 from -75°C to -70°C. The solution was warmed to room temperature and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride (50 ml) and dichloromethane (60 ml) to obtain the first organic layer and the aqueous layer, and the aqueous layer was extracted twice with dichloromethane (30 ml) to obtain the second organic layer . The first organic layer and the second organic layer were combined into 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 (EA:heptane=1:5) to obtain the product (5.5 g, 70%). The chemical shifts (δ) (unit: ppm) of the NMR hydrogen spectrum ( ¹ H-NMR (400 MHz, CDCl ₃ )) of the product are 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), 7.90 (s, 1H). It can be proved by the NMR hydrogen spectrum that Experimental Example 2 can prepare the intermediate of formula (6) in the foregoing disclosure, and its structure is named as (2S, 5S)-benzyl 5-(4-bromo-2-iodobenzyl)-2- tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate.

Next, the intermediate with formula (3) is prepared from the intermediate with formula (6). Please refer to the following reaction formula for the preparation process.

The preparation process will be described in detail below. DMSO (5 ml) was added to a 25 ml reaction vial and bubbled with argon for 30 minutes. The intermediate having formula (6) (500 mg), bis-pinacol borate (477 mg), potassium acetate (254 mg) and palladium catalyst Pd(dppf)Cl ₂ (31.3 mg) were added, and the reaction was continued under argon Bubble for 10 minutes. The solution was heated under argon, and the temperature of the solution was controlled to be 80° C. to allow the solution to react for 22 hours. 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 extracted twice with dichloromethane (15 ml) to obtain a second organic layer. The first organic layer and the second organic layer were combined into an organic layer extract, and the organic layer extract was extracted with water (15 ml). 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=1:7) to obtain the product (246 mg, 49%). The chemical shifts (δ) (unit: ppm) of the NMR spectrum ( ¹ H-NMR (400 MHz, CDCl ₃ )) of the product are 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), 7.79 (d, 1H, J = 2.4 Hz). It can be proved by the NMR hydrogen spectrum that Experimental Example 2 can prepare the intermediate of formula (3) in the foregoing disclosure, and its structure is named as (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.

Experimental example 3: preparation has the intermediate of formula (7)

Please refer to the following reaction formula for the preparation process of the intermediate with formula (7).

The preparation process will be described in detail below. Add the compound (200 mg) and THF (5 ml) of formula (10) into a 100 ml reaction bottle, namely (S)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1- Benzyl formate 1-formate and THF, the solution was stirred until the solute was completely dissolved. Lower the solution temperature to -75 °C to -70 °C under nitrogen. LDA solution (0.94 ml) was added dropwise to the solution, and the temperature was controlled at -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF/hexane. Keep the solution temperature at -75°C to -70°C and stir the mixture for 30 min. A mixture of 4-bromo-1-(bromomethyl)-2-fluorobenzene (4-bromo-1-(bromomethyl)-2-fluorobenzene) (209 mg) and THF (2 ml) was added dropwise to the solution, Control the solution temperature at -75°C to -70°C. The solution was warmed to room temperature and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride (10 ml) and dichloromethane (15 ml) to obtain the first organic layer and an aqueous layer, and the aqueous layer was extracted twice with dichloromethane (10 ml) to obtain the second organic layer . The first organic layer and the second organic layer were combined into 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 (EA: heptane=1:5) to obtain the product (105 mg, 30%). The chemical shifts (δ) (unit: ppm) of the NMR spectrum ( ¹ H-NMR (400 MHz, CDCl ₃ )) of the product are 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), 7.13- 7.17 (m, 2H). It can be proved from the NMR hydrogen spectrum that Experimental Example 3 can prepare the intermediate of formula (7) in the foregoing disclosure, and its structure is named as (2S, 5S)-tert-butyl 5-(4-bromo-2-fluorobenzyl)- 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate. The intermediate with formula (7) can be further reacted with double-linked pinacol borate, and the F group is replaced by a pinacol borate group. The product can be used to prepare FBPA. The reaction process can refer to Experimental Example 1 or Experimental Example 2.

Experimental example 4: preparation has the intermediate of formula (8)

Please refer to the following reaction formula for the preparation process of the intermediate with formula (8). The preparation process will be described in detail below. Add the compound (200 mg) and THF (5 ml) of formula (11) into a 100 ml reaction bottle, namely (S)-2-tert-butyl-3-methyl-4-oxoimidazolidine-1- Benzyl formate 1-carboxylate ((S)-benzyl 2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate) and THF, the solution was stirred until the solute was completely dissolved. Lower the solution temperature to -75 °C to -70 °C under nitrogen. LDA solution (0.83 ml) was added dropwise to the solution, and the temperature was controlled at -75°C to -70°C. In the LDA solution, the concentration of LDA was 1M, and LDA was dissolved in THF/hexane. Keep the solution temperature at -75°C to -70°C and stir the mixture for 30 min. 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 from -75°C to -70°C. The solution was warmed to room temperature and the solution was stirred for 16 hours. The solution was extracted with saturated aqueous ammonium chloride (10 ml) and dichloromethane (15 ml) to obtain the first organic layer and an aqueous layer, and the aqueous layer was extracted twice with dichloromethane (10 ml) to obtain the second organic layer . The first organic layer and the second organic layer were combined into 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 (EA: heptane=1:4) to obtain the product (77 mg, 23%). The chemical shifts (δ) (unit: ppm) of the NMR hydrogen spectrum ( ¹ H-NMR (400 MHz, CDCl ₃ )) of the product are 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), 7.35-7.39 (m, 5H). It can be proved from the NMR hydrogen spectrum that Experimental Example 4 can prepare the intermediate of formula (8) in the foregoing disclosure, and its structure is named as (2S, 5S)-benzyl 5-(4-bromo-2-fluorobenzyl)-2- tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate. The intermediate with formula (8) can be further reacted with double-linked pinacol borate, and the F group is replaced by a pinacol borate group. The product can be used to prepare FBPA. The reaction process can refer to Experimental Example 1 or Experimental Example 2.

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

Please refer to the following reaction formula for the preparation process.

The preparation process will be described in detail below. The intermediate with the structure of formula (2) is used as the starting material, and the fluorination reaction is carried out in the presence of the copper catalyst Cu(OTf) ₂ (py) ₄ , and the intermediate is reacted with K ¹⁸ F, so that the frequency on the aromatic ring The nicohol borate group was substituted ^by18F . In the fluorination reaction, the solvent is dimethylformamide (DMF), K ₂₂₂ is amino polyether, the reaction temperature is 110°C, and the reaction time is 20 minutes. This is followed by a borylation reaction in which the fluorinated intermediate is reacted with bis-pinacol borate ((Bpin) ₂ ) in the presence of a palladium catalyst Pd ₂ (dba) ₃ , whereby the - Br is substituted with a pinacol borate group. The palladium catalyst Pd ₂ (dba) ₃ uses P(Cy) ₃ as a ligand. In the borylation reaction, Pd ₂ (dba) ₃ and (Bpin) ₂ are soluble in dioxane (Dioxane), the solvent can be potassium acetate (KOAc) and water, the reaction temperature is 110°C, and the reaction time is 15 minutes . Carry out hydrolysis reaction next, make intermediate and hydrogen bromide (HBr) reaction, HBr can be pinacol borate group ( ) is hydrolyzed to -B(OH) ₂ , and the chiral auxiliary is hydrolyzed to an amino acid group. In the hydrolysis reaction, the reaction temperature was 150°C and the reaction time was 20 minutes.

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

Please refer to the following reaction formula for the preparation process.

The preparation process will be described in detail below. ¹⁸ F-labeled FBPA is prepared by using the intermediate having the structure of formula (3) as a starting material. For the reaction conditions of Experimental Example 6, please refer to the above-mentioned Experimental Example 5. The difference between Experimental Example 5 and Experimental Example 6 lies in the different starting materials, so the reaction process of Experimental Example 6 will not be repeated here.

In summary, the present disclosure provides a method for preparing a drug, an intermediate for synthesizing a drug, and a method for preparing the intermediate. Especially about the preparation method of ¹⁸ F-labeled FBPA, the intermediate used in the synthesis of FBPA and the preparation method of the intermediate. The preparation method of FBPA disclosed in the disclosure has a simple process, can effectively improve the efficiency and yield of FBPA synthesis, and FBPA can have good specific activity.

Although the disclosure has been described in some detail with reference to certain implementations, other implementations are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description of the embodiments contained herein.

It will be apparent to those having ordinary skill in the art that various modifications and changes can be made in the structure of this disclosure without departing from the scope or spirit of the disclosure. In view of the foregoing, the present disclosure is intended to cover modifications and variations of the disclosure which come within the scope of the appended claims.

none

none

Domestic deposit information (please note in order of depositor, date, and number) none Overseas storage information (please note in order of storage country, institution, date, and number) none

Claims (17)

An intermediate having a structure as shown in the following formula (1): Formula (1), wherein R ₁ is -Cl, -Br, -I, -OSO ₂ CF ₃ , -B(OH) ₂ or , R ₂ is -F, - ¹⁸ F, -Cl, -Br, -I, -SnMe ₃ , -SnBu ₃ , -B(OH) ₂ or , A is a chiral auxiliary. The intermediate as described in claim item 1, wherein A is or , wherein _A1 is C1-C8 alkyl, C7-C10 aralkyl or phenyl, _A2 is C1-C8 alkyl, and _A3 is C1-C8 alkyl. The intermediate as described in claim item 1, wherein A is Imidazolinone chiral auxiliary or bis-lactimide ether chiral auxiliary. The intermediate as claimed in item 2, wherein the intermediate has formula (2), formula (3), formula (4), formula (5), formula (6), formula (7) or formula (8) ) shows the structure: Formula (2), formula (3), Formula (4), Formula (5), Formula (6), Equation (7), or Formula (8). A method for preparing an intermediate, comprising: reacting a first reactant with a second reactant in an alkaline environment to obtain a first intermediate at a reaction temperature of -80°C to 0°C, wherein the The first reactant has a structure as shown in the following formula (9-1): Formula (9-1), R ₃ is -Cl, -Br, -I or -OSO ₂ CF ₃ , R ₄ is -F, -Cl, -Br, -I, -SnMe ₃ , -SnBu ₃ or -B (OH) ₂ , X is -Br or -I; and the second reactant has a structure as shown in the following formula (9-2) or formula (9-3): Formula (9-2), Formula (9-3), wherein A ₁ is a C1-C8 alkyl group, a C7-C10 aralkyl group or a phenyl group, A ₂ is a C1-C8 alkyl group, and A ₃ is a C1-C8 alkyl group. The method as claimed in item 5, wherein the second reactant has a structure as shown in the following formula (10), formula (11) or formula (12): formula (10), Equation (11) or Formula (12). The method according to claim 5, wherein reacting the first reactant with the second reactant in an alkaline environment comprises: mixing the first reactant, the second reactant with an organic metal base, the organic The metal base is selected from lithium diisopropylamide, n-butyllithium, lithium bis(trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidine, sodium methoxide, tertiary Lithium butoxide, sodium tertiary butoxide, potassium tertiary butoxide and sodium ethoxide and groups thereof. The method as claimed in item 5, wherein the first reactant has a structure as shown in the following formula (13) or formula (14): Equation (13) or Formula (14). The method according to claim 5, further comprising mixing the first reactant, the second reactant and an aprotic solvent. The method according to claim 9, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, methylene chloride and dioxane. The method as described in claim item 5, further comprising: The first intermediate is reacted with bis-linked pinacol borate in the presence of a palladium catalyst to obtain a second intermediate. The method according to claim 11, further comprising mixing the first intermediate, the bis-pinacol borate and an aprotic solvent. A method for preparing a drug, comprising: making the intermediate as described in claim 1 undergo a fluorination reaction with a fluorinating reagent to generate a first compound, wherein in the intermediate, R ₁ is -Cl, -Br , -I or -OSO ₂ CF ₃ , R ₂ is -Cl, -Br, -I, -SnMe ₃ , -SnBu ₃ , -B(OH) ₂ or . The method as described in claim item 13, wherein making the intermediate as described in claim item 1 and the fluorination reagent to perform the fluorination reaction comprises: in the presence of a copper catalyst, making the intermediate as described in claim item 1 and K ¹⁸ F reaction. The method according to claim 13, further comprising: performing a borylation reaction of the first compound with a borylation reagent to generate a second compound. The method as claimed in claim 15, wherein performing the borylation reaction of the first compound and the borylation reagent comprises: The first compound is reacted with bispinacol borate in the presence of a palladium catalyst. The method according to claim 15, further comprising: hydrolyzing the second compound.