A method for synthesizing 2-bromo-1-fluoro-4-iodobenzene

Abstract

The application relates to a synthesis method of 2-bromo-1-fluoro-4-iodobenzene, and the synthesis route is as follows: including the following steps: S1, dissolving 3-bromo-4-fluorobenzoic acid in an aqueous ammonia solution, adding a composite copper-based catalyst, mixing, placing in a closed system to carry out decarboxylation reaction, and obtaining 3-bromo-4-fluorobenzene; S2, dissolving 3-bromo-4-fluorobenzene prepared in step S1 in acetic acid, adding nitric acid and elemental iodine, mixing, placing in a closed system to carry out iodination reaction, and obtaining 2-bromo-1-fluoro-4-iodobenzene; wherein in the product treatment in step S2, the water phase separated by extraction is adjusted in pH by hydrochloric acid, an oxidizing agent is added to oxidize and precipitate coarse iodine, and the elemental iodine is collected by sublimation condensation. The application takes commercially available 3-bromo-4-fluorobenzoic acid as a starting material, obtains the target product through green decarboxylation and iodination, recycles the elemental iodine separated by extraction in the iodination step from the water phase to be used in the iodination reaction, so that the synthesis method of 2-bromo-1-fluoro-4-iodobenzene is safe in operation, high in yield, low in production cost and suitable for industrialized production.

Description

Technical Field

[0001] This application relates to the field of organic synthesis technology, and in particular to a method for synthesizing 2-bromo-1-fluoro-4-iodobenzene. Background Technology

[0002] 2-Bromo-1-fluoro-4-iodobenzene (CAS No.: 811842-30-5, molecular formula: C6H3BrFI, molecular weight: 300.9) is a polysubstituted benzene derivative containing three halogen substituents: bromine, fluorine, and iodine. Due to the presence of three halogen substituents with significantly different reactivity on its aromatic ring, site-selective functionalization is possible, enabling selective coupling reactions, Grignard reactions, and other reactions. Therefore, this compound, as a key haloaromatic intermediate, is widely used in drug molecule synthesis, organic optoelectronic material preparation, and various coupling reactions.

[0003] Currently, there are two main types of methods for synthesizing 2-bromo-1-fluoro-4-iodobenzene. One type is the diazotization-iodination route using 3-bromo-4-fluoroaniline as the starting material. This method first reacts 3-bromo-4-fluoroaniline with sodium nitrite under acidic conditions to generate a diazonium salt, and then iodizes it using iodine sources such as potassium iodide. However, while the diazonium salt is relatively stable in cold water, it easily decomposes upon heating and is prone to explosion during drying. The reaction is inefficient, lengthy, produces many byproducts, and requires cumbersome post-processing with low yields, making it unsuitable for industrial-scale production. The other type is the direct iodination route using 3-bromo-4-fluorobenzene as the starting material. This involves iodination via a system of elemental iodine and an oxidant. However, 3-bromo-4-fluorobenzene itself is not a readily available commercial chemical and requires multiple steps, including oxidative decarboxylation of 3-bromo-4-fluorotoluene or diazotization and deamination of 3-bromo-4-fluoroaniline. The difficulty in obtaining the raw materials limits the application of this route. In addition, the utilization rate of elemental iodine in this route is low, resulting in serious waste of iodine resources and further increasing production costs.

[0004] Therefore, providing a method for synthesizing 2-bromo-1-fluoro-4-iodobenzene that is readily available, involves simple steps, is safe to operate, has a high yield, low production cost, and is suitable for industrial production is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0005] In order to improve the reaction efficiency, yield and economy of the synthesis method of 2-bromo-1-fluoro-4-iodobenzene, and to overcome the defects of the prior art such as difficulty in obtaining raw materials, instability of diazonium salts, low iodine utilization, lengthy steps and difficulty in industrial production, this application provides a synthesis method of 2-bromo-1-fluoro-4-iodobenzene.

[0006] A synthetic method for 2-bromo-1-fluoro-4-iodobenzene, the synthetic route is as follows:

[0007] Includes the following steps: S1. Dissolve 3-bromo-4-fluorobenzoic acid in an ammonia-containing aqueous solution, add a composite copper-based catalyst and mix, place in a closed system, and carry out a decarboxylation reaction at 200-230℃. After the reaction is completed, cool, and filter the filtrate to adjust the pH with acid, extract, and distill under reduced pressure to obtain 3-bromo-4-fluorobenzene. S2. Dissolve the 3-bromo-4-fluorobenzene obtained in step S1 in acetic acid, add nitric acid and elemental iodine, mix, place in a closed system, and carry out the iodination reaction at 100-110℃. After the reaction is completed, quench, extract, concentrate under reduced pressure, and distill to obtain 2-bromo-1-fluoro-4-iodobenzene. In step S2, the aqueous phase separated by extraction is adjusted to pH 1.5-2.5 with hydrochloric acid, and an oxidant is added to oxidize and precipitate crude iodine. After sublimation and condensation, elemental iodine is collected.

[0008] The inventors discovered that using commercially available 3-bromo-4-fluorobenzoic acid as a starting material, 3-bromo-4-fluorobenzene can be generated in situ through decarboxylation catalyzed by a composite copper-based catalyst in an ammonia-containing aqueous solution. The resulting intermediate can be directly used in the subsequent iodination reaction without complex purification. This decarboxylation process avoids the preparation and separation of diazonium salt intermediates, eliminating the safety hazards of instability and explosiveness associated with diazonium salts. In the iodination step, elemental iodine is oxidized in nitric acid to form an electrophilic iodine species (I⁺), which electrophilically substitutes the aromatic ring of 3-bromo-4-fluorobenzene, introducing iodine atoms with high regioselectivity. Throughout the entire reaction process, the decarboxylation and iodination steps are conducted under mild conditions and do not interfere with each other, achieving a highly efficient connection from commercially available raw materials to the target product.

[0009] This application uses commercially available, low-cost 3-bromo-4-fluorobenzoic acid as the starting material. The decarboxylation reaction is carried out in an ammonia-containing aqueous solution using a composite copper-based catalyst in a one-step process to obtain 3-bromo-4-fluorobenzene. The decarboxylation reaction is conducted in a high-temperature liquid water medium containing ammonia. The composite copper-based catalyst (one or more of copper powder, cuprous oxide, and copper oxide) catalyzes the removal of CO2 from the carboxyl group under alkaline hydrothermal conditions. The only byproducts are CO2 and a small amount of ammonia gas, with no organic solvent emissions, making it environmentally friendly. The obtained 3-bromo-4-fluorobenzene can be obtained in high purity through simple extraction and vacuum distillation, and can be directly used in iodination reactions.

[0010] Furthermore, this application achieves the recovery and recycling of elemental iodine in the iodination step. After the iodination reaction, the iodine-containing aqueous phase separated by extraction is adjusted to pH with hydrochloric acid, and an oxidant (preferably hydrogen peroxide) is added to oxidize iodide ions to elemental iodine, which is then recovered after sublimation and condensation purification. The recovered iodine can be directly recycled for the next batch of iodination reactions. Through iodine recovery and recycling, the procurement cost of iodine sources is significantly reduced while ensuring the yield, and the discharge of iodine-containing wastewater is reduced, achieving a balance between economic and environmental benefits.

[0011] This application integrates a route of "decarboxylation of commercially available raw materials to prepare intermediates—iodination—iodine recovery cycle," effectively solving the technical problems of difficult raw material acquisition, unstable diazonium salts, low iodine utilization, lengthy steps, and difficulty in industrial production in existing technologies. It achieves high-yield, high-purity, low-cost, and environmentally friendly industrial production of 2-bromo-1-fluoro-4-iodobenzene without the need for diazotization, complex purification equipment, or large-scale one-time consumption of iodine sources.

[0012] In one specific implementation scheme, the mass concentration of liquid ammonia in the ammonia-containing aqueous solution in step S1 is 1-5 g / L.

[0013] By controlling the mass concentration of liquid ammonia in the ammonia-containing aqueous solution, a relatively suitable alkaline environment is maintained in the reaction system during the decarboxylation process. If the ammonia concentration is too low, the alkalinity is insufficient, and the decarboxylation reaction rate is easily affected. If the ammonia concentration is too high, the substrate 3-bromo-4-fluorobenzoic acid and its decarboxylation product 3-bromo-4-fluorobenzene may undergo hydrolysis or substitution side reactions under high-temperature alkaline conditions. For example, the bromine / fluorine substituents on the aromatic ring can be replaced by hydroxyl or amino groups under alkaline conditions. Simultaneously, the acid consumption required for acid neutralization after the reaction and the ammonia emissions tend to increase. Within the above concentration range, the decarboxylation reaction can proceed smoothly, with good product yield and purity, and the post-processing is simpler, thus improving the economic and environmental benefits of the process.

[0014] In one specific implementation, the mass of the ammonia-containing aqueous solution in step S1 is 2 to 8 times the mass of 3-bromo-4-fluorobenzoic acid.

[0015] By controlling the amount of ammonia-containing aqueous solution, the reaction system achieves both suitable substrate concentration and good mass transfer efficiency during the decarboxylation process. If the amount of ammonia-containing aqueous solution is too low, 3-bromo-4-fluorobenzoic acid is difficult to fully dissolve and disperse, resulting in insufficient contact between the reactants and the composite copper-based catalyst, limited mass transfer, and adversely affecting the progress of the decarboxylation reaction. If the amount is too high, the reactants and catalyst are excessively diluted, reducing the number of active sites per unit volume, leading to a decrease in the reaction rate, and simultaneously increasing the subsequent wastewater treatment volume and energy consumption. Within this dosage range, the substrate maintains a good dissolved and dispersed state, the catalyst activity is fully utilized, the decarboxylation reaction proceeds smoothly, the product yield and purity are both good, and the wastewater volume is moderate, making post-treatment more economical and efficient.

[0016] In one specific implementation scheme, the composite copper-based catalyst in step S1 is selected from two or more of copper powder, cuprous oxide, and copper oxide; preferably, the composite copper-based catalyst includes copper powder, cuprous oxide, and copper oxide; more preferably, the mass ratio of copper powder, cuprous oxide, and copper oxide is 1:(4-8):(0.5-1.5); more preferably, the mass ratio of copper powder, cuprous oxide, and copper oxide is 1:6:1; more preferably, the composite copper-based catalyst obtained by filtration in step S1 is directly reused.

[0017] The inventors discovered that when copper powder, cuprous oxide, and copper oxide coexist within a specific ratio range, their respective catalytic properties can complement each other. Cuprous oxide exhibits superior catalytic activity for decarboxylation reactions, but it is prone to valence state changes and gradual deactivation under high-temperature alkaline conditions. The presence of copper powder provides a reducing atmosphere during the reaction, inhibiting the conversion of cuprous oxide to copper oxide and helping to maintain the relative stability of active species in the system. Copper oxide, when used alone, has relatively weak activity, but it can be slowly converted into active species through the reduction effect of copper powder, thus supplementing and regulating the concentration of active sites. Each of the three components plays a different functional role; individual components have their own functional limitations. However, the combination of the three achieves functional complementarity, resulting in a relatively stable supply of active species during the reaction. The decarboxylation reaction can proceed continuously under relatively mild conditions, with a reasonable reaction time and good product yield and selectivity. Meanwhile, the aforementioned composite copper-based catalysts are all insoluble solids, which can be separated and recovered from the reaction system by simple filtration after the reaction. The recovered catalysts can be directly used in the next batch of reaction, realizing the reuse of catalysts, further reducing catalyst consumption costs, reducing solid waste generation, and are in line with the concept of green process.

[0018] Within the aforementioned ratio range, if the proportion of cuprous oxide is too low, there will be insufficient active sites in the reaction system, and the reaction rate will be easily affected. If the proportion of cuprous oxide is too high, the protective effect of copper powder in the system will be relatively insufficient, and the stability of active species under high temperature and alkaline conditions will be difficult to maintain. When the mass ratio of copper powder, cuprous oxide, and copper oxide is controlled within the above range, the functions of each component can be well coordinated and complementary, and the reaction rate and product yield are both ideal. Among them, a mass ratio of 1:6:1 is the best scheme, under which the functional matching degree among the three components is more suitable.

[0019] In one specific implementation, the molar ratio of 3-bromo-4-fluorobenzene to nitric acid in step S2 is 1:(1.5-2).

[0020] By controlling the molar ratio of 3-bromo-4-fluorobenzene to nitric acid, elemental iodine in the iodination reaction system is fully activated. Nitric acid acts as an oxidant in this reaction, oxidizing elemental iodine to electrophilic iodine species, thereby electrophilic iodination of the aromatic ring. If the amount of nitric acid is too low, the activation degree of elemental iodine is insufficient, the concentration of effective iodine species in the system is low, the iodination reaction proceeds slowly, the raw material conversion rate tends to decrease, and unactivated elemental iodine is more easily lost through volatilization during post-treatment, making it difficult to guarantee iodine utilization. If the amount of nitric acid is too high, the reaction system becomes too acidic, which may exacerbate side reactions of the substrate or product under high-temperature conditions, while also increasing the alkali consumption required for neutralization in post-treatment and wastewater discharge. Within this molar ratio range, elemental iodine can be sufficiently activated, the iodination reaction can proceed smoothly, the product yield is relatively good, the amount of waste acid is moderate, and post-treatment is more economical.

[0021] In one specific implementation, the molar ratio of 3-bromo-4-fluorobenzene to elemental iodine in step S2 is 1:(1.8-2).

[0022] By controlling the molar ratio of 3-bromo-4-fluorobenzene to elemental iodine, a relative balance is achieved between iodine source supply and reaction economy in the iodination reaction. Elemental iodine serves both as the iodizing agent, providing iodine atoms, and must be oxidized in nitric acid to become an electrophilic iodine species to substitute the aromatic ring. If the amount of elemental iodine is too low, the total amount of available iodine species in the system is insufficient, the conversion of raw materials is easily limited, the product yield tends to decrease, and unreacted 3-bromo-4-fluorobenzene needs to be recovered and reused, increasing the operational burden. If the amount of elemental iodine is too high, although a sufficient supply of iodine source is guaranteed, the excess iodine must be separated and removed from the system after the reaction, and the amount of iodine-containing waste liquid generated during post-treatment increases, leading to higher recovery costs. Within this molar ratio range, the iodine source supply meets the reaction requirements, the iodination reaction proceeds smoothly, the product yield is good, the excess iodine is relatively moderate, and post-treatment recovery is economical.

[0023] In one specific implementation, the oxidant is H2O2.

[0024] By using H2O2 as the oxidant for recovering elemental iodine from iodine-containing wastewater, iodide ions can be oxidized to elemental iodine without introducing additional impurity ions. The only byproduct is water, avoiding the problem of other oxidants (such as chlorine, hypochlorite, etc.) introducing metal salts or halide anions that affect the purity of the recovered iodine. The iodine recovered by H2O2 oxidation, after sublimation and condensation purification, can be directly returned to the iodination reaction step for recycling, without any adverse effect on the selectivity or yield of the iodination reaction. Furthermore, since H2O2 is a common industrial product, widely available and inexpensive, and excess H2O2 can be easily removed by heating during the recovery process, the operation is relatively simple, and the treated wastewater meets emission standards. This method achieves resource recovery of iodine without introducing additional impurities, improving both the environmental friendliness and economic efficiency of the overall process.

[0025] In summary, this application includes at least one of the following beneficial technical effects: 1. This application achieves the resource-based recycling of iodine by acidifying and oxidizing the extracted iodine-containing aqueous phase after the iodination reaction, precipitating crude iodine, and then refining it by sublimation and condensation to obtain elemental iodine, which is then directly recycled for the iodination reaction. This reduces the one-time consumption of iodine source and the discharge of iodine-containing waste liquid, effectively lowers the raw material cost, and improves both the economic and environmental aspects of the process.

[0026] 2. This application uses an ammonia-containing aqueous solution as the decarboxylation reaction medium and a composite copper-based catalyst to catalyze the removal of CO2 from 3-bromo-4-fluorobenzoic acid. The reaction byproducts are only CO2 and a small amount of ammonia, with no organic solvent emissions. Moreover, the composite copper-based catalyst is an insoluble solid, which can be recovered and reused after the reaction by simple filtration, reducing solid waste generation and catalyst consumption costs, thus embodying the concept of green process.

[0027] 3. This application utilizes a composite copper-based catalyst composed of copper powder, cuprous oxide, and copper oxide, which improves the conversion rate and selectivity of the decarboxylation reaction compared to any single component. Furthermore, this catalyst is simple to prepare, widely available, and inexpensive. With optimized control of the concentration and amount of ammonia solution and the reaction temperature, the decarboxylation step can proceed smoothly, resulting in good product yield and purity. Detailed Implementation

[0028] The present application will be further described in detail below with reference to embodiments and comparative examples: Some of the raw materials used in the examples and comparative examples: Raw material: 3-bromo-4-fluorobenzoic acid, CAS: 1007-16-5, purchased from Sigma-Aldrich.

[0029] Copper powder, cuprous oxide, and copper oxide, with particle sizes of 0.3-3μm and purity ≥99%, were purchased from Jinchang Zhongshengji New Materials Co., Ltd.

[0030] Unless otherwise specified, all raw materials used in the examples and comparative examples are commercially available products. Example Example 1

[0031] The synthesis method of 2-bromo-1-fluoro-4-iodobenzene is as follows: S1. Dissolve 100g (0.456mol) of 3-bromo-4-fluorobenzoic acid in 400g of ammonia-containing aqueous solution (the mass concentration of liquid ammonia in the ammonia-containing aqueous solution is 3g / L), add 8g of composite copper-based catalyst (obtained by mixing 1g of copper powder, 6g of cuprous oxide and 1g of copper oxide), mix to obtain a reaction solution, place the mixed solution in a sealed reaction vessel, heat to 215℃ and react for 3 hours. After the reaction is completed, cool to room temperature, filter to recover the composite copper-based catalyst, adjust the pH of the filtrate to 2 with hydrochloric acid, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and distill under reduced pressure to obtain 3-bromo-4-fluorobenzene; The weight of 3-bromo-4-fluorobenzene was calculated to be 74.7 g, with a yield of 93.6% and a liquid phase purity of 98.5%.

[0032] S2. Dissolve 100g of 3-bromo-4-fluorobenzene (0.571mol) obtained in step S1 in 200mL of acetic acid, add 275g (1.085mol) of elemental iodine and 65g (1.028mol) of nitric acid, mix to obtain a reaction solution, place the mixture in a sealed reaction vessel, heat to 105℃ and react for 3 hours, then react for 14 hours. After the reaction is completed, cool to room temperature, quench with saturated sodium sulfite solution, extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure at 38℃, and distill to obtain 2-bromo-1-fluoro-4-iodobenzene.

[0033] The weight of 3-bromo-4-fluorobenzene was calculated to be 89.3 g, with a yield of 52.0% and a liquid phase purity of 99.1%.

[0034] The aqueous phase separated by ethyl acetate extraction in step S2 was adjusted to pH 2.0 with hydrochloric acid, and 30% hydrogen peroxide was slowly added dropwise for oxidation. The mixture was stirred at 35°C for 1 hour, precipitating a black solid. The solid was then cooled to 25°C, centrifuged, and filtered to obtain wet crude iodine. The wet crude iodine was heated to 120°C for sublimation, and the iodine vapor was collected by condensation to obtain purified iodine.

[0035] According to the weighing calculation, the recovered elemental iodine was 192.3g. The total input of elemental iodine in this application was 275g. After deducting the 72.6g consumed in the reaction, the remaining unconsumed elemental iodine and iodide in the iodine-containing waste liquid was 202.4g. Therefore, the recovery rate of elemental iodine in this application was 95%. Example 2

[0036] The only difference between Example 2 and Example 1 is that in step S1 of Example 2, 400g of ammonia-containing aqueous solution (with a liquid ammonia concentration of 3g / L) is replaced with 400g of ammonia-containing aqueous solution (with a liquid ammonia concentration of 0.5g / L).

[0037] The weight of 3-bromo-4-fluorobenzene was calculated to be 60.2 g, with a yield of 75.4% and a liquid phase purity of 97.2%. Example 3

[0038] The difference between Example 3 and Example 1 is that in step S1 of Example 3, 400g of ammonia-containing aqueous solution (with a liquid ammonia concentration of 3g / L) is replaced with 400g of ammonia-containing aqueous solution (with a liquid ammonia concentration of 6g / L).

[0039] The weight of 3-bromo-4-fluorobenzene was calculated to be 68.5 g, with a yield of 85.8% and a liquid phase purity of 96.5%. Example 4

[0040] The only difference between Example 4 and Example 1 is that in step S1 of Example 4, 400g of ammonia-containing aqueous solution (with a liquid ammonia concentration of 3g / L) is replaced with 100g of ammonia-containing aqueous solution (with a liquid ammonia concentration of 3g / L).

[0041] The weight of 3-bromo-4-fluorobenzene was calculated to be 55.3 g, with a yield of 69.3% and a liquid phase purity of 95.8%. Example 5

[0042] The difference between Example 5 and Example 1 is that in step S1 of Example 5, 400g of ammonia-containing aqueous solution (with a liquid ammonia concentration of 3g / L) is replaced with 900g of ammonia-containing aqueous solution (with a liquid ammonia concentration of 3g / L).

[0043] The weight of 3-bromo-4-fluorobenzene was calculated to be 70.1 g, with a yield of 87.8% and a liquid phase purity of 97.8%. Example 6

[0044] The only difference between Example 6 and Example 1 is that in step S1 of Example 6, 8g of composite copper-based catalyst (obtained by mixing 1g of copper powder, 6g of cuprous oxide and 1g of copper oxide) is replaced with 8g of composite copper-based catalyst (obtained by mixing 6.5g of cuprous oxide and 1.5g of copper oxide).

[0045] The weight of 3-bromo-4-fluorobenzene was calculated to be 62.8 g, with a yield of 78.7% and a liquid phase purity of 96.0%. Example 7

[0046] The only difference between Example 7 and Example 1 is that in step S1 of Example 7, 8g of composite copper-based catalyst (obtained by mixing 1g of copper powder, 6g of cuprous oxide and 1g of copper oxide) is replaced with 8g of composite copper-based catalyst (obtained by mixing 4g of copper powder and 4g of copper oxide).

[0047] The weight of 3-bromo-4-fluorobenzene was calculated to be 40.5 g, with a yield of 50.7% and a liquid phase purity of 94.5%. Example 8

[0048] The only difference between Example 8 and Example 1 is that in step S1 of Example 8, 8g of composite copper-based catalyst (obtained by mixing 1g of copper powder, 6g of cuprous oxide and 1g of copper oxide) is replaced with 8g of composite copper-based catalyst (obtained by mixing 1.5g of copper powder and 6.5g of cuprous oxide).

[0049] The weight of 3-bromo-4-fluorobenzene was calculated to be 65.3 g, with a yield of 81.8% and a liquid phase purity of 96.8%. Example 9

[0050] The difference between Example 9 and Example 1 is that in step S2 of Example 9, 275g (1.085mol) of elemental iodine is replaced with 175g (0.690mol) of elemental iodine.

[0051] The weight of 3-bromo-4-fluorobenzene was calculated to be 85.9 g, with a yield of 50.0% and a liquid phase purity of 98.2%. Example 10

[0052] The only difference between Example 10 and Example 1 is that in step S2 of Example 10, 275g (1.085mol) of elemental iodine is replaced with 375g (1.478mol) of elemental iodine.

[0053] The weight of 2-bromo-1-fluoro-4-iodobenzene was 89.5 g, the yield was 52.1%, and its liquid phase purity was 98.5%. Example 11

[0054] The only difference between Example 11 and Example 1 is that in step S2 of Example 11, 65g (1.028mol) of nitric acid is replaced with 36g (0.571mol) of nitric acid.

[0055] The weight of 2-bromo-1-fluoro-4-iodobenzene was 58.4 g, the yield was 34.0%, and its purity was determined to be 96.5% by liquid chromatography. Example 12

[0056] The only difference between Example 12 and Example 1 is that in step S2 of Example 12, 65g (1.028mol) of nitric acid is replaced with 90g (1.428mol) of nitric acid.

[0057] The weight of 2-bromo-1-fluoro-4-iodobenzene was 77.3 g, the yield was 45.0%, and its purity was determined to be 97.0% by liquid chromatography.

[0058] Comparative Example 1 The only difference between Comparative Example 1 and Example 1 is that in step S1 of Comparative Example 1, 8g of composite copper-based catalyst (obtained by mixing 1g of copper powder, 6g of cuprous oxide and 1g of copper oxide) is replaced with 8g of copper powder.

[0059] The weight of 3-bromo-4-fluorobenzene was calculated to be 15.8 g, with a yield of 19.8% and a liquid phase purity of 92.0%.

[0060] Comparative Example 2 The only difference between Comparative Example 2 and Example 1 is that in step S1 of Comparative Example 2, 8g of composite copper-based catalyst (obtained by mixing 1g of copper powder, 6g of cuprous oxide and 1g of copper oxide) is replaced with 8g of cuprous oxide.

[0061] The weight of 3-bromo-4-fluorobenzene was calculated to be 43.5 g, with a yield of 54.5% and a liquid phase purity of 95.0%.

[0062] Comparative Example 3 The only difference between Comparative Example 3 and Example 1 is that in step S1 of Comparative Example 3, 8g of composite copper-based catalyst (obtained by mixing 1g of copper powder, 6g of cuprous oxide and 1g of copper oxide) is replaced with 8g of copper oxide.

[0063] The weight of 3-bromo-4-fluorobenzene was 12.2 g, the yield was 15.3%, and its purity was determined to be 90.5% by liquid chromatography.

[0064] The yields of S1 and S2, the overall yield, and the liquid phase purity of the target product, calculated by weighing during the synthesis of the target product in each embodiment, are summarized in Table 1 below: Table 1. Yields and liquid phase purity of the target products synthesized in each example

[0065] I. Effects of various parameters in the decarboxylation step on the reaction Combining the data from Examples 1-5 and Table 1, it can be seen that this application achieves a better yield of 3-bromo-4-fluorobenzene under suitable alkaline environment and mass transfer conditions by controlling the concentration of liquid ammonia and the amount of ammonia-containing aqueous solution. Specifically, Example 1, under conditions of a liquid ammonia concentration of 3 g / L and an ammonia-containing aqueous solution amount four times the substrate mass, exhibits superior yield and purity of 3-bromo-4-fluorobenzene compared to other examples, indicating that suitable alkalinity and substrate dispersion concentration are key factors for the smooth progress of the decarboxylation reaction. When the liquid ammonia concentration is too low, insufficient alkalinity limits the progress of the decarboxylation reaction; when the liquid ammonia concentration is too high, the substrate and product are prone to hydrolysis or substitution side reactions under high-temperature alkaline conditions. When the amount of ammonia-containing aqueous solution is too small, the system becomes too viscous, resulting in poor substrate dispersion; when the amount is too large, the substrate and catalyst are excessively diluted, leading to a decrease in the reaction rate.

[0066] Combining the data from Example 1 and Comparative Examples 1-3, and Table 1, it can be seen that the composition of the copper-based catalyst has a significant impact on the yield of the decarboxylation reaction. When using single copper powder, single cuprous oxide, or single copper oxide as catalysts, the yields were significantly lower than in Example 1. This indicates that when a single component is used as a catalyst, the catalytic activity is difficult to maintain due to the lack of functional synergy between the components. In contrast, Example 1 uses a combination of copper powder, cuprous oxide, and copper oxide. Through functional division and interconversion, the supply of active Cu⁺ species is continuously maintained, allowing the decarboxylation reaction to proceed smoothly, thereby achieving a higher yield and purity.

[0067] Combining the data from Examples 1 and 6-8, and Table 1, it can be seen that the integrity of the components in the copper-based catalyst also has a significant impact on the yield of the decarboxylation reaction. When any one of the three components is missing, the yield is significantly lower than in Example 1, indicating that the functional synergy between the components is disrupted, and the generation, maintenance, or replenishment of active species is missing, leading to a decrease in catalytic efficiency. The yield decrease is greatest when cuprous oxide is absent, further demonstrating the irreplaceable nature of cuprous oxide as the main active component.

[0068] II. The Influence of Various Parameters on the Reaction in the Iodination Step Combining the data from Examples 1 and 9-10 and Table 1, it can be seen that the amount of elemental iodine fed directly affects the yield of the iodination reaction. When the molar ratio of 3-bromo-4-fluorobenzene to elemental iodine is 1:1.2, the iodine source supply is insufficient, resulting in a low yield. Increasing the molar ratio to 1:1.9 significantly improves the yield; further increasing it to 1:2.6 causes the yield increase to plateau. This indicates that the effect of continuously increasing the amount of iodine on improving the yield gradually weakens. Therefore, controlling the molar ratio of 3-bromo-4-fluorobenzene to elemental iodine within the range of 1:(1.8-2.0) can achieve a better yield while considering the input cost and recovery burden of iodine.

[0069] Combining the data from Examples 1 and 11-12 and Table 1, it can be seen that the amount of nitric acid also has a significant impact on the yield of the iodination reaction. When the molar ratio of 3-bromo-4-fluorobenzene to nitric acid is 1:1.0, the nitric acid is insufficient to fully activate elemental iodine, resulting in a low yield. Increasing the molar ratio to 1:1.8 significantly improves the yield. Further increasing it to 1:2.5 results in excessive acidity in the system, increased side reactions, and a decrease in yield. This indicates that too little nitric acid leads to insufficient iodine activation, while too much increases side reactions. Controlling the molar ratio of 3-bromo-4-fluorobenzene to nitric acid within the range of 1:(1.5–2.0) allows for a more ideal yield in the iodination reaction.

[0070] III. The Effects of the Iodine Recovery Step Furthermore, this application achieves highly efficient recovery of elemental iodine by extracting and separating the iodine-containing aqueous phase after the iodination reaction, followed by acidification, hydrogen peroxide oxidation to precipitate crude iodine, and sublimation and condensation purification. The recovered iodine can be directly recycled for the next batch of iodination reaction, significantly reducing the procurement cost of iodine source and decreasing the discharge of iodine-containing wastewater.

[0071] IV. Overall Effect This application integrates a route for preparing intermediates from commercially available 3-bromo-4-fluorobenzoic acid through decarboxylation, iodination, and iodine recovery and recycling. Through synergistic optimization of parameters at each step, the overall yield and product purity of 2-bromo-1-fluoro-4-iodobenzene are both ideal, significantly superior to deviations and comparative schemes. Furthermore, this route eliminates the need for diazotization, avoiding the safety risks associated with the instability and explosiveness of diazonium salts. Both the copper-based catalyst and elemental iodine can be recovered and reused, further reducing production costs and waste emissions, demonstrating promising prospects for industrial application.

[0072] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A method for synthesizing 2-bromo-1-fluoro-4-iodobenzene, characterized in that, The synthesis route is as follows: Includes the following steps: S1. Dissolve 3-bromo-4-fluorobenzoic acid in an ammonia-containing aqueous solution, add a composite copper-based catalyst and mix, place in a closed system, and carry out a decarboxylation reaction at 200-230℃. After the reaction is completed, cool, and filter the filtrate to adjust the pH with acid, extract, and distill under reduced pressure to obtain 3-bromo-4-fluorobenzene. S2. Dissolve the 3-bromo-4-fluorobenzene obtained in step S1 in acetic acid, add nitric acid and elemental iodine, mix, place in a closed system, and carry out the iodination reaction at 100-110℃. After the reaction is completed, quench, extract, concentrate under reduced pressure, and distill to obtain 2-bromo-1-fluoro-4-iodobenzene. In step S2, the aqueous phase separated by extraction is adjusted to pH 1.5-2.5 with hydrochloric acid, and an oxidant is added to oxidize and precipitate crude iodine. After sublimation and condensation, elemental iodine is collected.

2. The method for synthesizing 2-bromo-1-fluoro-4-iodobenzene according to claim 1, characterized in that, The mass concentration of liquid ammonia in the ammonia-containing aqueous solution in step S1 is 1-5 g / L.

3. The method for synthesizing 2-bromo-1-fluoro-4-iodobenzene according to claim 1, characterized in that, The mass of the ammonia-containing aqueous solution in step S1 is 2-8 times the mass of 3-bromo-4-fluorobenzoic acid.

4. The method for synthesizing 2-bromo-1-fluoro-4-iodobenzene according to claim 1, characterized in that, The composite copper-based catalyst mentioned in step S1 is selected from two or more of copper powder, cuprous oxide and copper oxide.

5. The method for synthesizing 2-bromo-1-fluoro-4-iodobenzene according to claim 4, characterized in that, The composite copper-based catalyst comprises copper powder, cuprous oxide, and copper oxide.

6. The method for synthesizing 2-bromo-1-fluoro-4-iodobenzene according to claim 5, characterized in that, The mass ratio of the copper powder, cuprous oxide, and copper oxide is 1:(4-8):(0.5-1.5).

7. The method for synthesizing 2-bromo-1-fluoro-4-iodobenzene according to claim 1, characterized in that, The composite copper-based catalyst obtained by filtration in step S1 can be reused directly.

8. The method for synthesizing 2-bromo-1-fluoro-4-iodobenzene according to claim 1, characterized in that, The molar ratio of 3-bromo-4-fluorobenzene to nitric acid in step S2 is 1:(1.5-2).

9. The method for synthesizing 2-bromo-1-fluoro-4-iodobenzene according to claim 1, characterized in that, The molar ratio of 3-bromo-4-fluorobenzene to elemental iodine in step S2 is 1:(1.8-2).

10. The method for synthesizing 2-bromo-1-fluoro-4-iodobenzene according to claim 1, characterized in that, The oxidant is H2O2.

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