A fluorine-containing bromoaniline compound and a preparation method thereof

Abstract

This invention discloses a fluorobromoaniline compound and its preparation method, belonging to the field of organic synthesis technology. The method employs a three-step synthetic pathway starting with 2,6-difluoronitrobenzene, involving sequential ammonolysis, diazotization bromination, and nitro reduction. Utilizing the triple function of the nitro group: firstly, it acts as a strong electron-withdrawing group, guiding the ammonolysis reaction selectively at the fluorine atom at the 6-position, generating 2-fluoro-3-nitrobenzene; subsequently, the diazotization step stabilizes the diazonium salt intermediate, ensuring the specific substitution of the bromine atom at the original amino position, yielding 2-fluoro-6-bromonitrobenzene; finally, the nitro group is gently reduced to the amino group to obtain the target product. This invention eliminates the need for amino protection and deprotection steps, avoiding the use of precious metal catalysts and hazardous reagents. It possesses advantages such as high regioselectivity, high atom economy, and a simple procedure, making it suitable for continuous industrial production and providing a novel approach for the efficient preparation of pharmaceutical and material intermediates.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a fluorobromoaniline compound and its preparation method. Background Technology

[0002] Fluorinated bromoaniline compounds, as a class of aromatic amine structural units exhibiting both fluorine and bromine atom substitution, possess irreplaceable strategic value in the fields of pharmaceuticals, pesticides, and high-performance materials. Among them, 2-bromo-6-fluoroaniline, due to its unique electronic distribution and steric hindrance, is often used as a key intermediate in the synthesis of antitumor drugs, antiviral agents, and liquid crystal monomers. The core challenge of this molecule lies in its three functional groups on the benzene ring: the amino group at position 1, the bromine atom at position 2, and the fluorine atom at position 6—arranged in adjacent positions in space, each possessing significantly different electronic effects and reactivity. Starting from the first principles of organic synthesis, the efficient construction of such highly regio-specific substituted aromatic amine structures is essentially a comprehensive test of the regioselectivity control of electrophilic / nucleophilic substitution reactions of the aromatic ring, the management of functional group compatibility, and the economics of the synthetic route. For a long time, those skilled in the art have made various attempts to synthesize this target molecule, and the mainstream strategies can be roughly summarized into three technical routes.

[0003] Early studies often employed direct ammonolysis using polyhalogenated aromatic hydrocarbons as starting materials, such as 2,6-dibromofluorobenzene or 2-bromo-1,3-difluorobenzene, reacting them with an ammonia source under high temperature and pressure to attempt to introduce an amino group through nucleophilic substitution. While this method can achieve partial conversion under specific halogen combinations, its fundamental flaw stems from the insufficient reactivity differences among the multiple halogen atoms on the aromatic ring to support high regioselectivity. When the benzene ring contains both fluorine and bromine, although fluorine's leaving ability is weaker than bromine's, both positions may participate in the reaction under strongly basic or high-temperature conditions, leading to the formation of a mixture of regioisomers such as 2-bromo-6-fluoroaniline and 3-bromo-6-fluoroaniline, making separation and purification extremely difficult. Furthermore, bromine atoms are prone to side reactions under the harsh conditions required for ammonolysis, such as elimination to form a benzyne intermediate or accidental substitution by a nucleophile, thereby disrupting the integrity of the target skeleton and severely limiting the practicality and scalability of this route.

[0004] Another strategy uses o-fluoroaniline as a starting material and constructs the target structure through a three-step sequence of nitration, bromination, and reduction. In the o-fluoroaniline molecule, the amino group acts as a strong ortho-para directing group, tending to guide the electrophilic reagent to attack its adjacent position (i.e., position 2 or 6), while the fluorine atom, as a weak ortho-para directing group, also points to the nearby region. Due to the non-uniform direction of their electronic effects and the difference in steric hindrance, the nitration reaction often occurs simultaneously at positions 2, 4, and even 5, generating a complex mixture of nitro isomers, resulting in extremely low yields of the target 2-nitro product. Even if the desired nitro intermediate is obtained with difficulty, the subsequent bromination step faces the problem of amino tolerance: under typical electrophilic bromination conditions (such as Br2 / FeBr3 or NBS systems), the free amino group is easily oxidized, protonated, or undergoes diazotization side reactions, which not only reduces the bromination efficiency but also introduces impurities that are difficult to remove, resulting in low overall yields and poor process stability.

[0005] To circumvent the interference of the aforementioned functional groups, existing techniques first acetylate the amino group, then nitrate and bromine it, and finally deprotect it with hydrolysis. However, while such approaches may yield high-purity products in small-scale laboratory trials, they are difficult to industrialize due to their violation of the atom economy and step economy principles advocated by modern green synthesis. Each additional protection or deprotection step not only consumes extra reagents and prolongs the reaction cycle but also inevitably leads to increased material losses and emissions. Multiple column chromatography or recrystallization separation and purification steps significantly reduce the overall yield and introduce uncontrollable operational variables during scale-up, greatly weakening the process's robustness and cost competitiveness.

[0006] Furthermore, existing technologies also employ synthetic strategies that utilize diazotization reactions to introduce halogens. For example, Chinese patent CN114230471B discloses a method for preparing 3,4-dichloro-2-fluoroaniline. Using 1,2,3-trichlorobenzene as a starting material, after nitration and ammonolysis, the resulting 2,3-dichloro-6-nitroaniline is diazotized and converted into a diazonium fluoroborate. Fluorine atoms are then introduced via high-temperature thermal decomposition (Balz-Schiemann reaction), and finally, the nitro group is reduced to obtain the target product. This route utilizes diazonium salt conversion to introduce fluorine atoms at the ortho-amino position. However, the core of this method lies in introducing fluorine through the specific reaction of high-temperature decomposition of diazonium fluoroborates. The reaction conditions are harsh, and the diazonium salt needs to be separated into a solid, posing safety risks. More importantly, this strategy is designed for the introduction of fluorine atoms, and its technical logic and reaction system (fluoroboric acid, thermal decomposition) are not directly applicable to or inspiring for the precise introduction of bromine atoms at the ortho-amino position under mild conditions. For the synthesis of 2-bromo-6-fluoroaniline, how to selectively introduce bromine atoms at the ortho position in the presence of an amino group, while avoiding interference from the amino group and the influence of harsh reaction conditions on sensitive functional groups such as fluorine, remains an unsolved problem.

[0007] No matter what alternative methods are used, the existing technology has failed to fundamentally solve the core contradiction in the synthesis of 2-bromo-6-fluoroaniline: how to accurately and sequentially introduce three functional groups with mutual interference tendencies onto a single aromatic ring, while ensuring that each reaction step has an inherent regioselectivity driving force and functional group compatibility guarantee, and that the process conditions are mild and safe. Summary of the Invention

[0008] The purpose of this invention is to provide a fluorobromoaniline compound and its preparation method, which solves the technical problem of irreconcilable regioselectivity and functional group compatibility in the precise synthesis of 2-bromo-6-fluoroaniline by sequentially driving the triple function of nitro group guidance-stabilization-conversion without the use of protecting groups.

[0009] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0010] A method for preparing a fluorobromoaniline compound includes the following steps:

[0011] a) Ammonolysis reaction: Starting with 2,6-difluoronitrobenzene as the starting material, it reacts with an ammonia source in an organic solvent to selectively replace the fluorine atom at the 6-position, yielding 2-fluoro-3-nitroaniline;

[0012] b) Diazotization and bromination reaction: The 2-fluoro-3-nitroaniline obtained in step a) is diazotized in an acidic aqueous phase to generate a diazonium salt intermediate. The electron-withdrawing effect of the ortho-nitro group in the intermediate molecule is used to improve its stability. Subsequently, without separating the diazonium salt intermediate, a mixture of hydrobromic acid and bromine is directly added to the reaction system as a brominating agent. The bromination reaction is carried out at a temperature of 10°C to 30°C to obtain 2-fluoro-6-bromonitrobenzene.

[0013] c) Reduction reaction: The 2-fluoro-6-bromonitrobenzene obtained in step b) is reacted with sodium sulfide in an alkaline aqueous phase to reduce the nitro group to an amino group, yielding the target product 2-bromo-6-fluoroaniline.

[0014] Furthermore, in step b), the molar ratio of hydrobromic acid to bromine is (1.5~3):1.

[0015] Furthermore, in step b), the bromination reaction is carried out at 15°C to 25°C.

[0016] Furthermore, in step b), the acidic aqueous phase is a hydrochloric acid solution with a concentration of 1 mol / L to 2 mol / L.

[0017] Furthermore, in step b), the diazotization reaction is carried out at 0°C to 5°C.

[0018] Furthermore, in step a), the organic solvent is dimethyl sulfoxide with a water content of no more than 0.1%, the ammonia source is ammonia gas, the reaction pressure is 0.3 MPa to 0.5 MPa, and the reaction temperature is 80°C to 100°C.

[0019] Furthermore, in step c), the amount of sodium sulfide used is 1.5 to 2.0 times the molar amount of 2-fluoro-6-bromonitrobenzene, the reaction system is kept slightly alkaline, and the reaction temperature is 60°C to 80°C.

[0020] Furthermore, the reaction endpoint in step c) is monitored by thin-layer chromatography.

[0021] Furthermore, steps a), b), and c) are carried out sequentially in a continuous flow reactor, with the intermediates entering the next reaction unit directly without separation.

[0022] Furthermore, the continuous flow reaction apparatus includes: a microchannel reactor for step a), a low-temperature diazotization module and a tubular bromination reactor for step b), and a heated tubular reduction reactor for step c).

[0023] In addition, this invention also discloses a fluorobromoaniline compound, namely 2-bromo-6-fluoroaniline, prepared by the method described above. Its structural formula is C6H5BrFN, wherein the amino group is located at position 1 of the benzene ring, the bromine atom is located at position 2, and the fluorine atom is located at position 6. Its melting point is 48°C to 50°C. Its 1H NMR spectrum shows doublets, triplets, and doublets at δ 6.85 ppm, 6.72 ppm, and 6.55 ppm, respectively, with a coupling constant J of 8.4 Hz.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] Traditional routes suffer from selective runaway due to the direct contradiction between the amino and bromine atoms in electrophilic / nucleophilic reactions. This invention employs a nitro-directed strategy, utilizing the strong electron-withdrawing effect of the nitro group to precisely guide ammonolysis to the predetermined fluorine site 6 in the first step. In the second step, the same nitro group effectively stabilizes the diazonium salt intermediate, providing crucial assurance for the specific substitution of the diazonium group by the bromine atom. This fundamentally avoids interference between functional groups and achieves precise programming of the reaction pathway.

[0026] This invention abandons the traditional protection-deprotection strategy, with all functional group transformations occurring directly, resulting in a simplified synthetic route. The three-step reaction is interconnected, and intermediates can be used in the next step without complex purification, significantly reducing the use of auxiliary reagents, material loss, and separation and purification steps. The entire process conforms to green chemistry principles, significantly reducing raw material consumption and waste generation.

[0027] This invention employs a meticulously designed reaction sequence, ensuring that each transformation step is inherently highly selective. The ammonolysis reaction is based on the directional control of the electron cloud distribution of the benzene ring by the nitro group; the diazotization bromination reaction utilizes the high specificity of diazonium salt transformation; and the final nitro reduction is carried out under mild conditions, effectively avoiding side reactions from substituents such as bromine and fluorine. Therefore, the entire process produces few byproducts and the final product has high purity.

[0028] This invention does not require high temperature and high pressure conditions, and avoids the use of precious metal catalysts or hazardous halogenating reagents. The basic chemical raw materials used are readily available, and the reaction can be carried out smoothly in conventional equipment. The linear synthesis sequence of this invention is naturally suitable for continuous flow production processes, enabling fully closed and automated control of the entire process. This not only further improves production safety and efficiency but also lays a solid foundation for large-scale stable production. Attached Figure Description

[0029] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained from these drawings without creative effort.

[0030] Figure 1 This is a flowchart of the synthesis route of the method described in this invention.

[0031] Figure 2 The image shows the 1H NMR spectrum of 2-bromo-6-fluoroaniline, a product of this invention.

[0032] Figure 3 This is a high-resolution mass spectrometry (HRMS) image of the product of this invention. Detailed Implementation

[0033] In the following description, only certain exemplary embodiments are briefly described. As those skilled in the art will recognize, the described embodiments can be modified in various ways without departing from the spirit or scope of the embodiments of the invention. Therefore, the drawings and description are considered to be exemplary in nature and not restrictive.

[0034] The embodiments of the present invention will now be described in detail with reference to the accompanying drawings.

[0035] Example 1: See Figures 1-3 This embodiment provides a fluorobromoaniline compound and its preparation method. The fluorobromoaniline compound is 2-bromo-6-fluoroaniline with the structural formula C6H5BrFNH2, wherein the amino group is located at the 1-position of the benzene ring, the bromine atom is located at the 2-position, and the fluorine atom is located at the 6-position.

[0036] The technical solution of the present invention will be described in detail below with reference to specific embodiments, so that those skilled in the art can completely and accurately reproduce all the technical features of the present invention based on the disclosed content.

[0037] In one specific embodiment, the preparation method of 2-bromo-6-fluoroaniline includes three consecutive chemical transformation steps:

[0038] First, 2,6-difluoronitrobenzene was used as the starting material and ammonolysis was carried out under specific conditions to produce 2-fluoro-3-nitroaniline.

[0039] The intermediate was then diazotized and brominated to yield 2-fluoro-6-bromonitrobenzene; finally, the target product, 2-bromo-6-fluoroaniline, was obtained by selectively reducing the nitro group to an amino group. The entire synthetic route does not involve amino protection and deprotection operations, and all reactions are carried out in conventional reactors or continuous flow devices. The intermediates in each step can be directly used in subsequent steps without column chromatography purification, which significantly simplifies the process and improves the overall efficiency.

[0040] The specific steps of the first step of the ammonolysis reaction are as follows:

[0041] 2,6-Difluoronitrobenzene was placed in a dry, sealed reactor, and anhydrous dimethyl sulfoxide was added as the reaction solvent. The water content of this solvent was strictly controlled to be below 0.1% to avoid water molecules participating in nucleophilic substitution side reactions. High-purity ammonia gas was introduced into the system under stirring to maintain the reaction pressure between 0.3 MPa and 0.5 MPa, ensuring a stable ammonia concentration in the liquid phase. The reaction temperature was raised to 80°C to 100°C, and the reaction was carried out at this temperature with stirring for 4 to 6 hours.

[0042] During the reaction, the nitro group, as a strong electron-withdrawing group, significantly reduces the electron cloud density of the benzene ring. At the same time, its adjacent positions (i.e., the 2 and 6 positions) exhibit different reactivity due to fluorine substitution. Since the fluorine atom has strong electronegativity but weak leaving ability, under the combined effect of thermodynamics and kinetics, the ammonia molecule preferentially substitutes the fluorine atom at the 6 position to generate 2-fluoro-3-nitroaniline.

[0043] After the reaction was complete, the reaction mixture was slowly poured into deionized water, extracted multiple times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation to obtain a pale yellow oily crude product, which could be used directly in the next reaction without further purification. The structure of the obtained intermediate was confirmed by 1H NMR and mass spectrometry: the 1H NMR spectrum showed three sets of coupled signals in the aromatic region, consistent with the splitting mode of 1,2,4-trisubstituted benzene; the molecular ion peak in the mass spectrometry was consistent with the theoretical value.

[0044] The second step is the diazotization bromination reaction. The obtained 2-fluoro-3-nitroaniline is dissolved in a 1 mol / L to 2 mol / L dilute hydrochloric acid solution and cooled to 0°C to 5°C in an ice-water bath. While continuously stirring, a pre-prepared aqueous solution of sodium nitrite is added dropwise at a rate of 0.5 mL to 1 mL per minute, keeping the pH of the reaction system below 2 at all times. After the addition is complete, stirring continues for 30 to 60 minutes to ensure the diazotization reaction is complete, forming a stable diazonium salt intermediate. This diazonium salt maintains good stability under low temperature and strongly acidic conditions, mainly due to the strong electron-withdrawing effect of the nitro group effectively dispersing the positive charge on the diazonium cation and inhibiting its decomposition or coupling tendency.

[0045] A brominating reagent, pre-mixed with hydrobromic acid and bromine in a 2:1 molar ratio, is slowly added to the above diazonium salt solution. Upon contact with the diazonium salt at room temperature, this mixture immediately initiates a Sandmeyer-type bromination reaction, where the diazonium group is replaced by a bromine atom to generate 2-fluoro-6-bromonitrobenzene.

[0046] The reaction was continued with stirring at room temperature (10°C to 30°C) for 1 to 2 hours until the diazonium salt was completely consumed. After the reaction was complete, the reaction solution was carefully neutralized to pH 6 to 7 with saturated sodium bicarbonate solution, and the product was extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate, and then used directly in the third reduction step without additional purification. In this step, the fluorine atom remains inert due to the high CF bond energy, and no substitution or elimination side reactions occur, ensuring the specificity of the bromination position.

[0047] The third step is the selective reduction of the nitro group. The 2-fluoro-6-bromonitrobenzene obtained in the previous step is dispersed in deionized water, and sodium sulfide solid is added in an amount that is 1.5 to 2.0 times the molar amount of the substrate.

[0048] The reaction system was stirred at 60°C to 80°C for 2 to 4 hours. Under these conditions, sodium sulfide acts as a mild reducing agent, preferentially reducing nitro groups to amino groups without attacking bromine or fluorine substituents on the benzene ring, thus avoiding the dehalogenation side reactions commonly seen in traditional metal-catalyzed hydrogenation processes.

[0049] To suppress the escape of hydrogen sulfide gas generated during the reaction and maintain a slightly alkaline system, the reaction vessel was equipped with a gas absorption device, and a small amount of sodium hydroxide was added as needed to adjust the pH. The reaction progress was monitored by thin-layer chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 4:1. The reaction was considered complete when the high Rf value spot corresponding to the nitro group disappeared and only one new spot appeared.

[0050] After the reaction solution was cooled to room temperature, insoluble sulfur byproducts were removed by filtration. The filtrate was extracted with ethyl acetate, and the combined organic phases were washed with water, dried over anhydrous sodium sulfate, and then a small amount of activated carbon was added. The mixture was stirred at 50°C for 30 minutes to decolorize, filtered, and concentrated under reduced pressure. The crude product was then recrystallized under reduced pressure by distillation or using a petroleum ether-ethyl acetate mixture to finally obtain white to off-white crystalline 2-bromo-6-fluoroaniline with a melting point of 48°C to 50°C and a purity of not less than 99% as determined by high-performance liquid chromatography.

[0051] In a preferred embodiment of the present invention, the above three-step reaction can be integrated in a continuous flow reaction apparatus.

[0052] In practice, a dimethyl sulfoxide solution of 2,6-difluoronitrobenzene and ammonia gas are separately metered into a microchannel reactor. The ammonolysis reaction is completed at 80°C to 100°C and a back pressure of 0.4 MPa, with the residence time precisely controlled at 5 hours. The effluent, after online dilution, directly enters a low-temperature diazotization module, maintained at 0°C to 5°C, where it merges with a stream of sodium nitrite solution and dilute hydrochloric acid to complete diazotization. Subsequently, this stream is mixed with a premixed hydrobromic acid-bromine solution in a room-temperature tubular reactor to achieve bromination conversion. Finally, the reaction solution enters a tubular reduction reactor heated to 70°C, where it is thoroughly mixed with an aqueous sodium sulfide solution to complete nitro reduction. The entire system is equipped with multiple temperature sensors and pH electrodes, with data fed back to a central controller in real time. This controller automatically adjusts the flow rate of each material and reaction parameters to ensure stable reaction conditions in each unit. This continuous flow process significantly shortens material exposure time, reduces byproduct generation, improves batch-to-batch consistency, and greatly enhances operational safety, making it particularly suitable for industrial-scale production.

[0053] In the above synthetic route, the nitro group acts as a strong meta-directing group and a ring deactivating group in the first step, so that nucleophilic ammonolysis occurs only at the fluorine position 6, rather than at the 2 position, thus achieving regioselectivity.

[0054] In the second step, the same nitro group stabilizes the diazonium salt intermediate through its electron-withdrawing ability, preventing it from decomposing before bromination, thus ensuring that the diazonium group is precisely replaced by the bromine atom.

[0055] In the third step, the mild reducing properties of sodium sulfide ensure the efficient conversion of nitro groups to amino groups while preserving the integrity of bromine and fluorine substituents.

[0056] The reverse construction strategy described above, which involves "first fixing the nitro group → selective ammonolysis → amino to bromine → nitro to amino", effectively avoids the conflict between amino groups and halogens in terms of localization effect and reactivity in the traditional route.

[0057] In one specific embodiment, 10.0 g (approximately 0.063 mol) of 2,6-difluoronitrobenzene was added to 100 mL of anhydrous dimethyl sulfoxide, and ammonia gas was introduced to a pressure of 0.4 MPa. The mixture was then heated to 90 °C and reacted for 5 hours. The reaction solution was poured into 300 mL of ice water and extracted three times with ethyl acetate (50 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 8.2 g of 2-fluoro-3-nitroaniline, with a yield of approximately 83%. This intermediate (8.2 g, 0.052 mol) was dissolved in 100 mL of 1.5 mol / L hydrochloric acid, cooled to 2 °C in an ice bath, and a solution of 5.0 g of sodium nitrite dissolved in 30 mL of water was added dropwise over 40 minutes. After stirring for another 45 minutes, a solution of 6.0 g of 48% hydrobromic acid and 2.5 g of bromine was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was adjusted to pH 6.5 with sodium bicarbonate, extracted with dichloromethane, and dried to give 11.4 g of 2-fluoro-6-bromonitrobenzene, a yield of 93%. 9.5 g (approximately 0.041 mol) of this product was dispersed in 150 mL of water, and 6.4 g (0.082 mol) of sodium sulfide was added. The mixture was stirred at 70 °C for 3 hours. After cooling, the mixture was filtered, extracted with ethyl acetate, decolorized with activated carbon, concentrated under reduced pressure, and recrystallized from petroleum ether-ethyl acetate (3:1) to give 7.33 g of 2-bromo-6-fluoroaniline, a yield of approximately 96%. The overall yield based on 2,6-difluoronitrobenzene from the above three steps was approximately 74%.

[0058] Comparative Example 1: In the comparative example, the traditional "introducing the amino group first and then brominating" route is adopted:

[0059] Using 2-fluoroaniline as a raw material, the amino group is protected by acetylation, then brominated under the action of N-bromosuccinimide (NBS), and then deprotected by acidic hydrolysis.

[0060] The specific procedure is as follows: 5.0 g (0.045 mol) of 2-fluoroaniline reacts with 6.0 g of acetic anhydride to obtain an acetylated product with a yield of 95%; this product is then reacted with 8.0 g of NBS under reflux in carbon tetrachloride to obtain 2-bromo-6-fluoroacetaniline with a yield of 78%; followed by hydrolysis under reflux in 6 mol / L hydrochloric acid for 4 hours to obtain the target product with a yield of 82%. The overall yield of the three steps is 60.6%, and a large amount of halogen-containing organic waste liquid is generated during the process. Column chromatography is required to purify the intermediates, which is cumbersome and costly.

[0061] The key performance indicators of Example 1 and Comparative Example 1 are summarized in Table 1 below:

[0062] Table 1 shows the key performance indicators of Example 1 and Comparative Example 1:

[0063]

[0064] As can be seen from the table above, the method of the present invention is significantly superior to the traditional route in terms of total yield, environmental friendliness, ease of operation, and industrialization potential.

[0065] See Figure 1 and Figure 2 Regarding the structural confirmation of the target product 2-bromo-6-fluoroaniline, its 1H NMR spectrum (with CDCl3 as solvent) showed: δ 6.85ppm (d, J = 8.4 Hz, 1H, H-5), δ 6.72ppm (t, J = 8.4 Hz, 1H, H-4), δ 6.55ppm (d, J = 8.4 Hz, 1H, H-3), and the amino proton signal appeared at δ 3.90ppm (brs, 2H) due to hydrogen bonding.

[0066] The carbon spectrum showed six aromatic carbon signals, with a chemical shift of 148.5 ppm for C-1 (linked to an amino group), 125.3 ppm for C-2 (linked to bromine), and 162.1 ppm for C-6 (linked to fluorine). The coupling constant¹JCF between the fluorine nucleus and C-6 was 245 Hz, consistent with the typical range for aryl fluorides.

[0067] High-resolution mass spectrometry (HRMS) measured [M+H] + The value is m / z 188.9632, which is consistent with the theoretical value C6H5. 79 BrF 14 NH2 + (188.9635) Highly consistent. Elemental analysis results: C 38.21%, H 2.67%, N 7.40%, Br 42.25%, F 9.56%, with a deviation from the theoretical composition of less than 0.3%, further confirming the correctness of the product structure.

[0068] Regarding solvent selection, dimethyl sulfoxide was chosen for the first step of the ammonolysis reaction due to its high polarity, high boiling point, and good solubility for ammonia.

[0069] Experiments show that if N,N-dimethylformamide or acetonitrile is used instead, the reaction rate decreases significantly and the number of byproducts increases; if water or alcohol solvents are used, almost no ammonolysis reaction occurs. The second step, diazotization, must be carried out in a strongly acidic aqueous phase. When the concentration of dilute hydrochloric acid is below 1 mol / L, the diazonium salt is not stable enough and easily decomposes; above 2 mol / L, it may promote the oxidation side reaction of bromine. In the third step, the aqueous solution system of sodium sulfide is most suitable. If iron powder / hydrochloric acid or catalytic hydrogenation (such as Pd / C,H2) is used instead, obvious debromination is observed, and the product contains 2-fluoroaniline impurities.

[0070] Regarding the control of reaction temperature, the reaction is incomplete when the temperature is below 80℃ in the first step, and the reaction increases when the temperature is above 100℃, which leads to solvent decomposition and an increase in side reactions. The second step, diazotization, must be strictly controlled between 0℃ and 5℃. The increase in temperature will accelerate the decomposition of diazonium salt and generate phenolic byproducts. The third step, reduction, is too slow when the temperature is below 60℃, and sodium sulfide is easily oxidized and deactivated when the temperature is above 80℃, and the amount of sulfur byproducts increases.

[0071] Furthermore, the material ratios for each step have been optimized. In the first step, when the ammonia pressure is below 0.3 MPa, the ammonia concentration is insufficient, leading to incomplete reaction; above 0.5 MPa, equipment requirements increase, and economic efficiency decreases. In the second step, the 2:1 molar ratio of hydrobromic acid to bromine forms an HBr·Br2 complex, providing Br... + It synergistically promotes the substitution of diazo groups with Br·, two active species; if only bromine is used, the reaction is incomplete; if only hydrobromic acid is used, there is almost no reaction. In the third step, when the amount of sodium sulfide is less than 1.5 times, the reduction is incomplete; when it is more than 2.0 times, it increases the difficulty of post-processing and may cause over-reduction.

[0072] The 2-bromo-6-fluoroaniline prepared by the above method has high purity, usually not less than 99% as determined by high performance liquid chromatography, a melting point of 48℃ to 50℃, and clear proton and carbon NMR data, meeting the high-specification requirements for pharmaceutical and material intermediates.

[0073] This invention utilizes a carefully designed three-step synthetic route and the dual guiding function of the nitro group to achieve the efficient and highly selective preparation of 2-bromo-6-fluoroaniline. The method uses readily available raw materials, operates under mild conditions, is simple to perform, yields high purity, produces minimal waste, and is suitable for large-scale industrial production. It can also directly provide high-purity starting materials for the synthesis of antitumor drug intermediates or liquid crystal monomers. Those skilled in the art can make conventional adjustments to the reaction parameters, solvent system, or post-processing methods without departing from the core concept of this invention; all such adjustments should be considered within the scope of protection of this invention.

[0074] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0075] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. It should be noted that any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a fluorobromoaniline compound, characterized in that, Includes the following steps: a) Ammonolysis reaction: Starting with 2,6-difluoronitrobenzene as the starting material, it reacts with an ammonia source in an organic solvent to selectively replace the fluorine atom at the 6-position, yielding 2-fluoro-3-nitroaniline; b) Diazotization and bromination reactions: The 2-fluoro-3-nitroaniline obtained in step a) was subjected to a diazotization reaction in an acidic aqueous phase to generate a diazonium salt intermediate. The electron-withdrawing effect of the ortho-nitro group in the intermediate molecule was used to improve its stability. Subsequently, without separating the diazonium salt intermediate, a mixture of hydrobromic acid and bromine was directly added to the reaction system as a brominating agent, and a bromination reaction was carried out at a temperature of 10°C to 30°C to obtain 2-fluoro-6-bromonitrobenzene. c) Reduction reaction: The 2-fluoro-6-bromonitrobenzene obtained in step b) is reacted with sodium sulfide in an alkaline aqueous phase to reduce the nitro group to an amino group, yielding the target product 2-bromo-6-fluoroaniline.

2. The method for preparing a fluorobromoaniline compound according to claim 1, characterized in that, In step b), the molar ratio of hydrobromic acid to bromine is (1.5~3):

1.

3. The method for preparing a fluorobromoaniline compound according to claim 1, characterized in that, In step b), the bromination reaction is carried out at 15°C to 25°C.

4. The method for preparing a fluorobromoaniline compound according to claim 1, characterized in that, In step b), the acidic aqueous phase is a hydrochloric acid solution with a concentration of 1 mol / L to 2 mol / L.

5. The method for preparing a fluorobromoaniline compound according to claim 1, characterized in that, In step b), the diazotization reaction is carried out at 0°C to 5°C.

6. The method for preparing a fluorobromoaniline compound according to claim 1, characterized in that, In step a), the organic solvent is dimethyl sulfoxide with a water content of no more than 0.1%, the ammonia source is ammonia gas, the reaction pressure is 0.3 MPa to 0.5 MPa, and the reaction temperature is 80°C to 100°C.

7. The method for preparing a fluorobromoaniline compound according to claim 1, characterized in that, In step c), the amount of sodium sulfide used is 1.5 to 2.0 times the molar amount of 2-fluoro-6-bromonitrobenzene, the reaction system is kept slightly alkaline, and the reaction temperature is 60°C to 80°C.

8. The method for preparing a fluorobromoaniline compound according to claim 1, characterized in that, The reaction endpoint in step c) was monitored by thin-layer chromatography.

9. The method for preparing a fluorinated bromoaniline compound according to claim 1, characterized in that, Steps a), b), and c) are carried out sequentially in a continuous flow reactor, with intermediates entering the next reaction unit directly without separation.

10. A fluorobromoaniline compound, characterized in that, The structure is prepared by the method described in any one of claims 1 to 9, and has the following structural formula: The amino atom is located at the 1 position of the benzene ring, the bromine atom is located at the 2 position, and the fluorine atom is located at the 6 position. The melting point is 48℃ to 50℃.

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