A method for preparing an 18F-FBPA precursor

Abstract

The application discloses a kind of 18 The application discloses a preparation method of F-FBPA precursor, which is used for preparing 4-bromo-2-nitrobenzaldehyde and comprises the following steps: S1, under alkaline conditions and preset temperature conditions, a raw material mixture is added into a mixture containing NaIO4 at a first rate for reaction to obtain a first mixture containing 4-bromo-2-nitrobenzaldehyde; S2, the first mixture is separated and purified to obtain solid 4-bromo-2-nitrobenzaldehyde; in step S1, the raw material mixture comprises (E)-1-(4-bromo-2-nitrostyryl) pyrrolidine and a first solvent. The application solves the technical problem that the reported preparation method for preparing 4-bromo-2-nitrobenzaldehyde is not suitable for industrial production. The preparation method of the application has mild reaction conditions and simple operation, is suitable for industrial production, and the chemical purity of the prepared 4-bromo-2-nitrobenzaldehyde reaches 99.8%.

Description

Technical Field

[0001] This invention relates to the field of boron-containing drugs, specifically to a... 18 Preparation method of F-FBPA precursor. Background Technology

[0002] Boron neutron capture therapy (BNCT) is a rapidly developing precision medicine technology in the international oncology field in recent years, and it is also one of the most advanced cancer treatments in the world. Its principle is to utilize… 10 B captures neutrons, undergoes a nuclear reaction, and releases high-energy rays that kill cancer cells.

[0003] One of the essential conditions for BNCT to be effective is a boron-containing drug with high tumor targeting. 4-Boron-L-phenylalanine (L-BPA) (…) Figure 1 L-BPA is the world's first and only approved BNCT drug. To better screen patients using PET imaging, study the metabolic process of L-BPA in the body, and monitor its biodistribution in real time, positron emission tomography (PET) is often used in actual research and application. 18 F-labeled L-BPA obtained 18 F-FBPA serves as a companion diagnostic to L-BPA, a boron-containing drug with high tumor targeting efficacy, to enable the selection of treatment timing for BNCT, evaluation of treatment efficacy, and real-time monitoring of the drug during BNCT treatment.

[0004] at present, 18 F-FBPA is often prepared using 4-bromo-2-nitrobenzaldehyde as a key precursor through various chemical reactions. 18 In the F-FBPA process, the quality of the raw material 4-bromo-2-nitrobenzaldehyde significantly affects the yield. 18 F-FBPA has a significant impact on the quality of finished products.

[0005] As BNCT gradually advances to widespread application, the demand for 4-bromo-2-nitrobenzaldehyde will also gradually increase. However, the currently reported preparation methods for 4-bromo-2-nitrobenzaldehyde are not suitable for industrial production, for example, due to low yield and high cost, the risk of explosion of raw materials, the use of heavy metal materials in the preparation process causing serious pollution, or the generation of byproducts that are difficult to remove.

[0006] Therefore, it is necessary to improve the preparation method of 4-bromo-2-nitrobenzaldehyde so that it is suitable for industrial production, achieving technical effects such as increasing yield while reducing costs, avoiding the generation of by-products, and ensuring safety and pollution-free production. Summary of the Invention

[0007] The purpose of this invention is to provide a 18 The method for preparing F-FBPA precursor aims to address the technical problems of existing methods for preparing 4-bromo-2-nitrobenzaldehyde, which are unsuitable for industrial production. These problems include low yield and high cost, explosion risks of raw materials, serious pollution caused by the use of heavy metal materials in the preparation process, and the generation of byproducts that are difficult to remove.

[0008] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0009] This invention provides 18 A method for preparing the F-FBPA precursor, used to prepare 4-bromo-2-nitrobenzaldehyde, includes the following steps:

[0010] S1. Under alkaline conditions and a preset temperature, the raw material mixture is added dropwise to a mixture containing NaIO4 at a first rate to react and obtain a first mixture containing 4-bromo-2-nitrobenzaldehyde.

[0011] S2. The first mixture is separated and purified to obtain solid 4-bromo-2-nitrobenzaldehyde;

[0012] In step S1, the raw material mixture includes (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine and a first solvent.

[0013] Preferably, step S2, the separation and purification of the first mixture includes the following steps:

[0014] S2.1 Separate the solute from the first mixture to obtain a crude solid product containing 4-bromo-2-nitrobenzaldehyde;

[0015] S2.2 Add the first solvent system to the crude solid product containing 4-bromo-2-nitrobenzaldehyde and heat it to a preset temperature to obtain a second mixture;

[0016] S2.3 Filter and wash the filter cake with a third solvent to obtain a second filtrate. Cool the second filtrate to crystallize and filter. Dry the filter cake to obtain solid 4-bromo-2-nitrobenzaldehyde.

[0017] Preferably, in step S2.2, the first solvent system includes the third solvent and the fourth solvent; the volume ratio of the third solvent to the fourth solvent is in the range of 1:1 to 3:1.

[0018] Preferably, in step S2.2, a third solvent is first added to the crude solid product containing 4-bromo-2-nitrobenzaldehyde and mixed evenly, and then a fourth solvent is added dropwise at a second rate.

[0019] Preferably, the second rate is 50-70 drops / minute.

[0020] Preferably, the third solvent is one of ethanol, dichloromethane, ethyl acetate, methyl tert-butyl ether, dichloromethane, isopropyl acetate, acetone, and acetonitrile; and the fourth solvent is one of pure water, n-heptane, and petroleum ether.

[0021] Preferably, the preset temperature range in step S2.2 is 70~90℃, and the second filtrate is cooled to 0~5℃ in step S2.4.

[0022] Preferably, the molar ratio of (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine to NaIO4 is in the range of 2.0 to 4.0.

[0023] Preferably, the first solvent is one of THF, 2-MeTHF, Dioxane, and DMSO.

[0024] Preferably, the (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine is synthesized by adding N,N-dimethylformamide dimethylacetal and pyrrole to a DMF solution of 4-bromo-2-nitrotoluene.

[0025] The present invention has the following beneficial effects: The present invention provides a method for preparing pharmaceutical grade 4-bromo-2-nitrobenzaldehyde. The method has mild reaction conditions, short route, simple operation and simple post-processing operation, and is suitable for industrial production. It solves the technical problem that the reported preparation methods for 4-bromo-2-nitrobenzaldehyde are not suitable for industrial production. The chemical purity of the prepared 4-bromo-2-nitrobenzaldehyde product reaches 99.8%. Attached Figure Description

[0026] To make the objectives, technical solutions, and advantages of the invention clearer, the invention will now be described in further detail with reference to the accompanying drawings, wherein:

[0027] Figure 1 This is a schematic diagram of the synthetic route of 4-bromo-2-nitrobenzaldehyde in Example 1 of the present invention.

[0028] Figure 2 This is a schematic diagram of the synthetic route of 4-bromo-2-nitrobenzaldehyde in Example 5 of the present invention.

[0029] Figure 3 This is a schematic diagram of the HPLC detection results in Example 5 of the present invention.

[0030] Figure 4 This is a schematic diagram of the nuclear magnetic resonance detection results in Embodiment 5 of the present invention. Detailed Implementation

[0031] To more clearly illustrate the objectives, technical solutions, and advantages of the embodiments of the present invention, the technical solutions in the embodiments of the present invention will be described in detail and completely below with reference to the accompanying drawings. It should be noted that the same reference numerals and letters in the drawings represent similar components; once a component is defined in one drawing, it will not be defined and explained again in subsequent drawings.

[0032] This invention can be applied to a 18 The preparation of 4-bromo-2-nitrobenzaldehyde, the precursor of F-FBPA, solves the technical problems of the reported preparation methods for 4-bromo-2-nitrobenzaldehyde, which are not suitable for industrial production. These problems include low yield and high cost, explosion risk of raw materials, serious pollution caused by the use of heavy metal materials in the preparation process, and the generation of byproducts that are difficult to remove.

[0033] The technical concept of this invention is:

[0034] (1) Mechanism of action of L-BPA.

[0035] In the treatment process of BNCT, firstly, the carriers are... 10 When a targeted drug based on beta-2 (a stable, non-radioactive natural isotope) is injected into the human body, the selectivity of the targeted drug allows... 10 B highly specifically accumulates within tumor tissue; then, the tumor site is externally irradiated with a targeted low-energy hyperthermal neutron beam, after which the tumor tissue... 10 B is activated and undergoes boron neutron capture, releasing alpha particles and... 7 Li particles, with a range of only 10 micrometers (about the size of a cancer cell) and high energy line density, cause the DNA double helix structure of tumor cells to break and kill them, thus achieving targeted killing of cancer cells at the cellular level without damaging normal tissue.

[0036] (2) 18 Mechanism of action of F-FBPA.

[0037] Accumulation in cells via the L-amino acid transporter (LAT1), which is highly expressed in human cancer tissues but almost not expressed in other normal organs, therefore... 18 F - FBPA can also be used as a novel amino acid PET imaging agent for the diagnosis of various tumors, especially brain tumors and malignant mesothelioma. (Research) 18 Labeling methods and optimized labeling conditions for efficient preparation of F-FBPA18 F-FBPA can provide strong support for the widespread application of BNCT technology and tumor diagnosis.

[0038] In 2023, Chun-Yi Wu et al. used 4-bromo-2-nitrobenzaldehyde as a key precursor and obtained the desired product through nucleophilic substitution, reduction, HI substitution, asymmetric alkylation, coupling, and hydrolysis. 18 F-FBPA.

[0039] Therefore, 4-bromo-2-nitrobenzaldehyde, as a key precursor, needs to be subject to quality control as an active pharmaceutical ingredient and its production process needs to be developed in accordance with my country's "Technical Guidelines for Pharmaceutical Research of Radioactive Chemical Generic Drugs".

[0040] (3) The inventors have discovered the following problems in the existing synthesis technology of 4-bromo-2-nitrobenzaldehyde.

[0041] Method 1: CN101362697 uses 4-bromo-2-nitrotoluene as a raw material. It first reacts with N,N-dimethylformamide dimethylacetal and pyrrole to convert it into an enamine intermediate. Then, it is oxidized with 27.5% hydrogen peroxide and a phase transfer catalyst, benzyltriethylammonium bromide, to obtain 4-bromo-2-nitrobenzaldehyde with a yield of 81.5% and a purity of 98.7%. This method uses readily available raw materials, but hydrogen peroxide, as a peroxide, is a controlled substance and poses an explosion risk, making it unsuitable for industrial production.

[0042] Method 2: (Synthetic Communications, 2001, 31, 3721-3727) Using 4-bromo-2-nitrotoluene as a raw material, it first generates a diacetate intermediate through oxidation with CrO3-AcOH, and then obtains 4-bromo-2-nitrobenzaldehyde through acidic hydrolysis. This method uses CrO3 as an oxidant, which generates a large amount of chromium-containing wastewater, causing serious pollution.

[0043] Method 3: (Journal of Materials Chemistry C, 2021, 9, 4200-4205) Using 4-bromo-2-nitrotoluene as raw material, methyl dibromination is achieved using HBr, followed by hydrolysis to obtain aromatic formaldehyde. This method produces many impurities and generates monobromo and tribromo byproducts that are difficult to remove.

[0044] Method 4: (Synthetic Communications, 2014, 31, 3721-3727) Using o-nitrobenzaldehyde as a raw material, bromination occurs under the action of NaBr, sodium periodate and concentrated sulfuric acid to obtain 4-bromo-2-nitrobenzaldehyde. This method easily generates byproducts of bromination at different positions, which are difficult to remove.

[0045] In summary, the inventors have found that existing methods for synthesizing 4-bromo-2-nitrobenzaldehyde suffer from problems such as low yield and high cost, explosive risks of raw materials, serious pollution caused by the use of heavy metal materials in the preparation process, and the generation of byproducts that are difficult to remove. Moreover, most of the purification methods are used for experimental research and employ column chromatography. Although column chromatography can yield 4-bromo-2-nitrobenzaldehyde that meets experimental requirements, scaling up laboratory column chromatography equipment to small-scale, pilot-scale, and production line equipment in industrial production presents technical problems such as complex operation, high maintenance costs, large eluent consumption, and difficulty in recovering raw materials, making it highly unsuitable for industrial production.

[0046] Therefore, with the promotion of BNCT, the industrial synthesis of 4-bromo-2-nitrobenzaldehyde needs to reduce the use of raw materials, reduce the difficulty of operation and dimensional complexity, and minimize production costs while ensuring chemical purity.

[0047] Based on this, the present invention provides a method for preparing pharmaceutical grade 4-bromo-2-nitrobenzaldehyde. This method has mild reaction conditions, a short route, simple operation, and simple post-processing, making it suitable for industrial production. It solves the technical problem that the currently reported preparation methods for 4-bromo-2-nitrobenzaldehyde are not suitable for industrial production. The chemical purity of the prepared 4-bromo-2-nitrobenzaldehyde product reaches 99.8%.

[0048] To further illustrate the preparation method of the present invention, the following application examples are disclosed.

[0049] Example 1, please refer to Figure 1 This embodiment provides a 18 The preparation method of F-FBPA precursor includes the following steps:

[0050] S1. Under alkaline conditions and a preset temperature, the raw material mixture is added dropwise to a mixture containing NaIO4 at a first rate to react and obtain a first mixture containing 4-bromo-2-nitrobenzaldehyde.

[0051] S2. The first mixture is separated and purified to obtain solid 4-bromo-2-nitrobenzaldehyde;

[0052] In step S1, the raw material mixture includes (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine and a first solvent.

[0053] In this embodiment, (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine can undergo an oxidation reaction with NaIO4.

[0054] In this embodiment, the alkaline condition refers to the pH range of the solution of the raw material mixture and the mixture containing NaIO4 being 9-11 during the reaction.

[0055] In this embodiment, the specific temperature refers to a reaction temperature ≤20°C. Specifically, the reason for maintaining the temperature below 20°C is that the reaction system will release heat due to the addition of NaIO4 solution, so it is necessary to keep the temperature below 20°C to ensure experimental safety.

[0056] In this embodiment, the first rate is 60-100 drops / minute. Specifically, the volume of one drop of solution is 0.04-0.06 ml.

[0057] In this embodiment, preferably, the molar ratio of (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine to NaIO4 is in the range of 2.0 to 4.0.

[0058] In this embodiment, the mixture containing NaIO4 is prepared by adding NaIO4 to an aqueous solution of THF, wherein the volume ratio of NaIO4 to the aqueous solution of THF is 1:1.

[0059] In this embodiment, preferably, the first solvent is one of THF, 2-MeTHF, Dioxane, and DMSO, with THF being the preferred solvent.

[0060] Example 2, based on Example 1, further defines step S2. In step S2, the separation and purification of the first mixture includes the following steps:

[0061] S2.1 Separate the solute from the first mixture to obtain a crude solid product containing 4-bromo-2-nitrobenzaldehyde;

[0062] S2.2 Add the first solvent system to the crude solid product containing 4-bromo-2-nitrobenzaldehyde and heat it to a preset temperature to obtain a second mixture;

[0063] S2.3 Filter and wash the filter cake with a third solvent to obtain a second filtrate. Cool the second filtrate to crystallize and filter. Dry the filter cake to obtain solid 4-bromo-2-nitrobenzaldehyde.

[0064] The technical solution of this embodiment utilizes the synergistic effect of two solvents with significantly different polarities (a third solvent and a fourth solvent) to regulate the solubility of the target compound in stages, thereby achieving a selective crystallization purification method. The principle is as follows: Utilizing the solvent polarity gradient, the target compound and impurities are fully dissolved in the third solvent under elevated temperature conditions. Then, in the fourth solvent, the overall polarity of the mixed system is significantly reduced, creating a sufficient polarity gradient between the third and fourth solvents. This drives a sharp drop in the solubility of the target compound, minimizing its overall solubility.

[0065] Specifically, the chemical purity of the 4-bromo-2-nitrobenzaldehyde solid obtained in step S2.2 is ≥97%.

[0066] Specifically, in this embodiment, S2.1, separating the solute from the first mixture includes the following steps:

[0067] S2.1.1 Filter the first mixture to obtain a first filtrate, add a second solvent to the first filtrate, the second solvent being an organic solvent, and separate the liquid to collect the organic phase, the organic phase including 4-bromo-2-nitrobenzaldehyde and impurities; specifically, the second solvent is one of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, dichloromethane, dioxane, n-butyl acetate, and acetonitrile.

[0068] S2.1.2 Wash the organic phase with pure water, and then remove the second solvent under reduced pressure to obtain a solid crude product containing 4-bromo-2-nitrobenzaldehyde.

[0069] In this embodiment, preferably, in step S2.2, the first solvent system includes the third solvent and the fourth solvent; the volume ratio of the third solvent to the fourth solvent is in the range of 1:1 to 3:1, preferably the volume ratio of the third solvent to the fourth solvent is 3:2.

[0070] Specifically, in this embodiment, the third solvent is one of ethanol, dichloromethane, ethyl acetate, methyl tert-butyl ether, dichloromethane, isopropyl acetate, acetone, and acetonitrile; the fourth solvent is one of pure water, n-heptane, and petroleum ether. Specifically, the third and fourth solvents are used in combination, preferably ethanol / pure water, dichloromethane / n-heptane, ethyl acetate / n-heptane, methyl tert-butyl ether / n-heptane, dichloromethane / n-heptane, isopropyl acetate / petroleum ether, acetone / n-heptane, acetonitrile / n-heptane, and more preferably dichloromethane / n-heptane, ethyl acetate / n-heptane, acetone / n-heptane, and acetonitrile / n-heptane.

[0071] In this embodiment, preferably, in step S2.2, a third solvent is first added to the crude solid containing 4-bromo-2-nitrobenzaldehyde and mixed thoroughly, and then a fourth solvent is added dropwise at a second rate. The purpose of adding the third solvent first is to dissolve 4-bromo-2-nitrobenzaldehyde, which requires a high solubility. The purpose of adding the fourth solvent is to change the polarity of the solution, causing the target compound to precipitate. The steps include: first, completely dissolving the crude solid containing 4-bromo-2-nitrobenzaldehyde in the third solvent; then, continuously adding the fourth solvent until the solution becomes slightly turbid, and then adding the third solvent again to bring it back to a clear state, ensuring that 4-bromo-2-nitrobenzaldehyde is in a critical state for precipitation in the solution. Throughout this process, the solution temperature is maintained at a preset temperature to ensure the solubility of the target compound. Preferably, the second rate is 50-70 drops / minute. Specifically, the volume of one drop of solution is 0.04-0.06 ml.

[0072] In this embodiment, preferably, the preset temperature range in step S2.2 is 70~90℃, and the second filtrate is cooled to 0~5℃ in step S2.3. Specifically, the cooling process involves first naturally cooling to room temperature and then using a low-temperature reactor to cool to 0~5℃, preferably to 0℃. In actual preparation, it was observed that the product precipitation was highest and the yield was the highest when the temperature was reduced to 0℃.

[0073] Example 3, based on Example 2, preferably uses ethanol as the third solvent and pure water as the fourth solvent. In step S2.2, ethanol is first added to the crude solid containing 4-bromo-2-nitrobenzaldehyde and mixed evenly. Then, pure water is added dropwise at a rate of 50-70 drops / minute until the solution becomes slightly turbid. Then, 1-2 mL of hot ethanol is added back to the solution until it becomes clear. In step S2.3, the solution is filtered and the filter cake is washed with ethanol to obtain a second filtrate. The second filtrate is first cooled naturally to room temperature and then cooled to 0-5°C using a low-temperature reactor to crystallize and filter. The filter cake is then dried to obtain solid 4-bromo-2-nitrobenzaldehyde. The chemical purity of the solid 4-bromo-2-nitrobenzaldehyde obtained according to the above steps is ≥99%.

[0074] Example 4, based on any one of Examples 1 to 3, preferably, is synthesized by adding N,N-dimethylformamide dimethylacetal and pyrrole to a DMF solution of 4-bromo-2-nitrotoluene.

[0075] In this embodiment, the (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine is synthesized through the following steps:

[0076] A1. Add N,N-dimethylformamide dimethylacetal and pyrrole to a DMF solution of 4-bromo-2-nitrotoluene, and the reaction pH is approximately 9-11;

[0077] A2. Stir and heat to 100~120℃ for 3~5 hours. During this period, an enamination reaction occurs, and the system is a dark red solution.

[0078] A3. Cooling and depressurization remove volatile organic compounds, yielding the residue;

[0079] A4. Add pure water to the residue obtained in step A3. When solid substances are observed to precipitate, start to gradually cool down and continue stirring before filtering. After washing the filter cake with water, crude (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine is obtained.

[0080] Specifically, the molar ratio range for each raw material is: N,N-dimethylformamide dimethyl acetal : pyrrole : 4-bromo-2-nitrotoluene = 1.1:1.1:1 ~ 1.5:1.5:1.5

[0081] Specifically, the yield of (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine synthesized using the above steps was 99%.

[0082] Specifically, the common name for (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine is bromonitrostyrylpyrrolidine.

[0083] Specifically, the crude (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine obtained does not require purification and can be directly used to prepare 4-bromo-2-nitrobenzaldehyde.

[0084] Example 5, based on the technical solutions of Examples 1, 2, 3, and 4, experimentally verifies the preparation method using multiple sets of data. Specifically, the values ​​of each raw material and its proportion are taken from the low, medium, and high ranges, as shown in the table below:

[0085]

[0086] As can be seen from the table above, the preparation method disclosed in this invention can achieve the technical effects of no secondary pollution, simple operation, high yield of target product, and high purity of target product. It is very suitable for industrial production and has great significance in application and promotion.

[0087] The following section provides a detailed description of one of the optimal implementation methods (Experimental Group 2). Please refer to [link / reference]. Figure 2 :

[0088] (1) Preparation of intermediate: (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine

[0089] The raw materials were prepared in the following molar ratio: N,N-dimethylformamide dimethyl acetal : pyrrole : 4-bromo-2-nitrotoluene = 1.2 : 1.2 : 1. 4-bromo-2-nitrotoluene was dissolved in DMF, and the reaction was carried out at pH 9.

[0090] First, N,N-dimethylformamide dimethyl acetal (87 mL, 655 mmol) and pyrrole (55 mL, 655 mmol) were added to 300 mL of 4-bromo-2-nitrotoluene (116 g, 536 mmol) in DMF, and the reaction was carried out at pH 9.

[0091] Then, stir and heat to 110°C for 3 hours;

[0092] Then, cool down to 60 degrees Celsius. o C, Removal of volatile organic compounds by reducing pressure;

[0093] Then, 800 mL of pure water was added to the residue, and (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine was observed to precipitate; the mixture was stirred continuously for 20-30 min, and then gradually cooled to 0 °C. o C. Continue stirring for 20-30 minutes, filter, wash the filter cake with water to obtain crude (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine, which can then be used directly to prepare 4-bromo-2-nitrobenzaldehyde.

[0094] (2) Preparation of 4-bromo-2-nitrobenzaldehyde

[0095] The alkaline conditions are: reaction pH=9, the preset temperature is below 20℃, and the first solvent is a THF solution;

[0096] First, under the above reaction conditions, a THF solution of crude (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine was added dropwise at a rate of 1 drop / second to a mixture containing NaIO4. The mass of NaIO4 was 347 g, the molar mass was 1.62 mol, and the molar ratio of (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine to NaIO4 was 3.0. After the addition was complete, a first mixture containing 4-bromo-2-nitrobenzaldehyde was obtained.

[0097] Then, the reaction system was stirred for 8-10 h at a temperature below 20 °C. The insoluble salts were removed by filtration using a sand core and a 1000-mesh funnel.

[0098] Then, using ethyl acetate as the second solvent, the first mixture was washed with 200 mL of ethyl acetate, the filtrate was separated, and the organic phase was collected.

[0099] Then, the organic phase was washed with 900 mL of pure water, and then ethyl acetate was removed under reduced pressure.

[0100] Then, 300 mL of ethanol and 300 mL of pure water were added to the residue after the removal of ethyl acetate, followed by 15 g of activated carbon for pigment adsorption, decolorization, and purification. The mixture was then heated to 80°C. o C, stir for 30-40 minutes;

[0101] Then, filter while hot to obtain a second filtrate. The remaining filter cake is washed with 30 mL of anhydrous ethanol, and the second filtrate is heated to 80°C. o C, dissolved;

[0102] Then, gradually cool down to 0. o C. Stirring to induce crystallization, with a stirring time of 20-30 min;

[0103] Then, the filter cake of the target material was washed with 30 mL of anhydrous ethanol.

[0104] Then, the target filter cake is placed in a forced-air drying oven 45. o Drying at C for 2-3 h yielded 128.1 g of 4-bromo-2-nitrobenzaldehyde (85% yield), which was characterized as a pale yellow solid.

[0105] The 4-bromo-2-nitrobenzaldehyde prepared in this example was analyzed by HPLC and NMR, and the results are as follows: Figure 3 and Figure 4 As shown in the figure. The chemical purity, as determined by HPLC, is above 99.0%.

[0106] (1) The parameter settings for HPLC detection are as follows:

[0107] Take an appropriate amount of the reaction solution of this product, add diluent (methanol) to dissolve and quantitatively dilute to prepare a 1 mg / ml solution.

[0108] Operating procedure: Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512, High Performance Liquid Chromatography.

[0109] Main instruments: High performance liquid chromatograph, electronic balance (d=0.1mg).

[0110] Reagent solution: Methanol (HPLC).

[0111] Chromatographic conditions: Octadecylsilane and pentafluorophenyl bonded silica gel was used as the packing material (Horizon C18 / PFP, 4.6×250mm, 5µm or equivalent column); water was used as mobile phase A and methanol as mobile phase B, and gradient elution was performed according to the following table: detection wavelength was 220nm; column temperature was 40℃; flow rate was 1.000ml per minute; injection volume was 10µl.

[0112]

[0113] like Figure 3 As shown in the HPLC spectrum, the peak with a retention time of 16.096 min is the peak of 4-bromo-2-nitrobenzaldehyde, with a peak area of ​​16760.47 mAu*s and a peak area ratio of 99.85%. The chemical purity of 99% can be obtained by using the peak area ratio of HPLC.

[0114] (2) The NMR detection of compound 4-bromo-2-nitrobenzaldehyde 1 H-NMR The data is as follows:

[0115] 1 ¹H NMR (400 MHz, CDCl₃) δ 10.37 (s, 1H), 8.26 (d, J = 1.6 Hz, 1H), 7.94 – 7.92 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H). Please refer to [reference needed]. Figure 4 The NMR spectrum shows that δ 10.37 represents the hydrogen atom of the aldehyde group, and δ 8.26, 7.94–7.92, and 7.84 represent hydrogen atoms on the benzene ring. This confirms that the product obtained is indeed 4-bromo-2-nitrobenzaldehyde.

[0116] In a comparative example, concentrated sulfuric acid (324 mL) was slowly added to a solution of 4-bromo-2-nitrotoluene (300 g, 1.38 mol) in acetic anhydride (2400 mL) at 0 °C. Then, a solution of chromium trioxide (384 g, 3.8 mol) in acetic anhydride (2160 mL) was added, maintaining the internal temperature below 10 °C. After stirring for 1 h, the contents of the flask were poured into an ice-water mixture, the solid was filtered, and the washings were washed with water until the washings were colorless. The product was suspended in 1800 mL of a 2% sodium carbonate aqueous solution with stirring. After thorough mixing, the solid was filtered, washed with water, and dried under reduced pressure. The suspension of the diacetate obtained in the previous step in a mixture of 1360 mL concentrated hydrochloric acid, 1250 mL water, and 480 mL ethanol was refluxed for 45 min. The mixture was then cooled to room temperature, the solid was filtered and washed with water to give 4-bromo-2-nitrobenzaldehyde (147 g, 45% yield in two steps), a brown solid with an HPLC purity of 93%.

[0117] As can be seen from the above comparative examples, the technical solution of this invention can achieve higher yields and higher purity of the target product. Compared with the column chromatography purification process used in the prior art, the preparation method of this invention has mild reaction conditions, a short route, simple operation, and simple post-processing, making it suitable for industrial production. It solves the technical problem that the reported preparation methods for 4-bromo-2-nitrobenzaldehyde are not suitable for industrial production, and the chemical purity of the prepared 4-bromo-2-nitrobenzaldehyde product reaches 99.8%.

[0118] This invention has been illustrated through several embodiments. Those skilled in the art should understand that various modifications, adjustments, or equivalent substitutions can be made to the features in these embodiments without departing from the core spirit and scope of this invention. The scope of protection of this invention should not be limited to the specific embodiments disclosed herein. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort should fall within the scope of protection of this invention.

Claims

1. A kind 18 A method for preparing the F-FBPA precursor, used to prepare 4-bromo-2-nitrobenzaldehyde, characterized in that... Includes the following steps: S1. Under alkaline conditions and a preset temperature, the raw material mixture is added dropwise to a mixture containing NaIO4 at a first rate to react and obtain a first mixture containing 4-bromo-2-nitrobenzaldehyde. S2. The first mixture is separated and purified to obtain solid 4-bromo-2-nitrobenzaldehyde; In step S1, the raw material mixture includes (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine and a first solvent.

2. As described in claim 1 18 The method for preparing the F-FBPA precursor is characterized by... In step S2, the separation and purification of the first mixture includes the following steps: S2.1 Separate the solute from the first mixture to obtain a crude solid product containing 4-bromo-2-nitrobenzaldehyde; S2.2 Add the first solvent system to the crude solid product containing 4-bromo-2-nitrobenzaldehyde and heat it to a preset temperature to obtain a second mixture; S2.3 Filter and wash the filter cake with a third solvent to obtain a second filtrate. Cool the second filtrate to crystallize and filter. Dry the filter cake to obtain solid 4-bromo-2-nitrobenzaldehyde.

3. As described in claim 2 18 The method for preparing the F-FBPA precursor is characterized by... In step S2.2, the first solvent system includes the third solvent and the fourth solvent; the volume ratio of the third solvent to the fourth solvent is in the range of 1:1 to 3:

1.

4. The method according to claim 3 18 The method for preparing the F-FBPA precursor is characterized by... In step S2.2, a third solvent is first added to the crude solid product containing 4-bromo-2-nitrobenzaldehyde and mixed evenly, and then a fourth solvent is added dropwise at a second rate.

5. The method according to claim 3 18 The method for preparing the F-FBPA precursor is characterized by... The second rate is 50-70 drops / minute.

6. The method according to claim 3 18 The method for preparing the F-FBPA precursor is characterized by... The third solvent is one of ethanol, dichloromethane, ethyl acetate, methyl tert-butyl ether, dichloromethane, isopropyl acetate, acetone, and acetonitrile; the fourth solvent is one of pure water, n-heptane, and petroleum ether.

7. The method according to claim 2 18 The method for preparing the F-FBPA precursor is characterized by... The preset temperature range mentioned in step S2.2 is 70~90℃, and the second filtrate is cooled to 0~5℃ in step S2.

4.

8. The method according to claim 1 18 The method for preparing the F-FBPA precursor is characterized by... The molar ratio of (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine to NaIO4 is in the range of 2.0 to 4.

0.

9. The method according to claim 1 18 The method for preparing the F-FBPA precursor is characterized by... The first solvent is one of THF, 2-MeTHF, Dioxane, and DMSO.

10. The claim 1 18 The method for preparing the F-FBPA precursor is characterized by... The (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine is synthesized by adding N,N-dimethylformamide dimethylacetal and pyrrole to a DMF solution of 4-bromo-2-nitrotoluene.

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