A fluorine-containing hydroxybenzoic acid compound and a preparation method thereof

Abstract

The application belongs to the technical field of organic synthesis chemistry, and particularly relates to a fluorine-containing hydroxybenzoic acid compound and a preparation method. The application provides a novel synthesis path, which takes 4-fluoro-3-methoxybenzonitrile as a starting material, firstly performs specific demethylation reaction in benzene or toluene solvent through anhydrous aluminum chloride catalysis to obtain an intermediate 4-fluoro-3-hydroxybenzonitrile; then performs acid hydrolysis reaction on the intermediate in a mixed medium of concentrated sulfuric acid and water to convert the cyano group into a carboxyl group, and obtains 3-hydroxy-4-fluorobenzoic acid crude product; finally, high-purity product is obtained through directional recrystallization of an ethanol-water mixed solvent. The application fundamentally avoids competitive bromination and Grignard reagent application of a traditional route, and has the remarkable advantages of simple route, mild condition, safe operation, high selectivity, environmental friendliness and easy industrial implementation.

Description

Technical Field

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

[0002] 3-Hydroxy-4-fluorobenzoic acid is a key fluorinated aromatic building block for the synthesis of various drugs, pesticides, and high-performance materials. The unique electronic configuration and coordination environment formed by the ortho-phenolic hydroxyl group and fluorine atom in its molecule are crucial for the bioactivity, metabolic stability, and physicochemical properties of downstream molecules. With the increasing demands from downstream applications for raw material purity, cost, and green production, developing an efficient, highly selective synthetic route suitable for large-scale production has become a long-standing core technological bottleneck in this field.

[0003] The industry and academia generally adopt the classic synthetic route using p-fluorobenzoic acid as the starting material, which usually includes the following two core steps: electrophilic bromination of p-fluorobenzoic acid on the benzene ring to obtain the key intermediate 3-bromo-4-fluorobenzoic acid; subsequently, the brominated product reacts with metallic magnesium to form a Grignard reagent, which is then carboxylated with carbon dioxide, and finally acidified to obtain the target product.

[0004] However, in practical use, there are two interrelated and irreconcilable fundamental flaws that make its industrial application face insurmountable problems:

[0005] First, there is the inherent contradiction of uncontrollable regioselectivity: the first step of the aromatic electrophilic bromination reaction has serious problems in principle. The substrate p-fluorobenzoic acid simultaneously possesses a fluorine atom (ortho- and para-directing groups, but strongly passivating the benzene ring) and a carboxyl group (meta-directing group, with even stronger passivating ability). The directing effects of these two groups conflict with each other, resulting in a double passivation effect on the benzene ring. This makes the attack of the electrophile (bromocation) lack a clear selectivity, inevitably generating a mixture of isomers of 3-bromo and 5-bromo, as well as polybrominated byproducts. Because these isomers have extremely similar physicochemical properties, subsequent separation and purification are extremely difficult, leading to low yields, high costs, and difficulty in consistently controlling the purity of the final product. This defect stems from the electronic structure of the substrate molecule itself, belonging to the level of uncontrolled regioselectivity at the chemical principle level, and cannot be eradicated through simple process optimization.

[0006] Secondly, there are serious limitations in process safety and scalability: the second step, the Grignard reaction, inherently requires an absolutely anhydrous and oxygen-free environment to maintain the high reactivity of the organomagnesium reagent. While this chemical characteristic can be controlled on a laboratory scale, scaling it up to industrial production translates into extremely stringent requirements for equipment, operation, and control. The introduction of trace amounts of water and oxygen not only leads to reagent inactivation and a sharp drop in yield but also poses significant safety risks such as combustion and explosion. To achieve this step, expensive dedicated reaction systems and strict process monitoring are necessary, making it difficult to meet the requirements of modern green chemical production in terms of both economy and safety.

[0007] In summary, existing mainstream technical approaches are caught in a dual dilemma due to the inherent contradictions in their underlying reaction mechanisms: poor front-end selectivity makes separation difficult, while high-risk back-end operations restrict scalability.

[0008] Existing technologies (such as CN108863775B) disclose methods for demethylating fused-ring carboxylic acids (such as 6-methoxy-1-naphthoic acid) to prepare phenolic hydroxyl compounds using Lewis acids (such as aluminum trichloride). However, this method is for fused-ring systems, and the reaction is carried out in high-temperature polar solvents (such as DMF). When this method is directly transferred to monobenzene-ring fluorinated systems containing strongly electron-withdrawing cyano groups, the chemical stability of the cyano group in strong Lewis acids and at high temperatures, as well as the selectivity of the demethylation reaction, are completely unknown and highly uncertain. Existing technologies do not provide any insights or successful examples.

[0009] Existing technologies (such as CN1358708A and CN109678741B) disclose methods for preparing benzoic acid by hydrolyzing fluorinated benzonitrile, but these only address the source of the carboxyl group and do not address how to efficiently and selectively introduce phenolic hydroxyl groups at specific positions on the benzene ring. Even considering combining the two known reactions of "demethylation" and "nitrile hydrolysis," technicians still face a critical decision hurdle: whether to "hydrolyze the nitrile group first to obtain methoxybenzoic acid, then demethylate" or "demethylate first to obtain hydroxybenzonitrile, then hydrolyze." Existing technologies do not teach which order to choose and why within the specific molecular framework of fluorine- and cyanide-containing groups. In particular, if hydrolysis is chosen first, the resulting intermediate 4-fluoro-3-methoxybenzoic acid may undergo uncontrollable side reactions such as decarboxylation and Friedel-Crafts acylation under subsequent strong Lewis acid demethylation conditions, raising questions about the feasibility of the pathway. Summary of the Invention

[0010] The purpose of this invention is to provide a fluorinated hydroxybenzoic acid compound and its preparation method, which solves the technical problems of poor regioselectivity, low process safety due to dependence on Grignard reagents, and difficulty in industrial scale-up in the synthesis of 3-hydroxy-4-fluorobenzoic acid in the prior art.

[0011] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0012] A method for preparing a fluorinated hydroxybenzoic acid compound involves a specific functional group sequential transformation, using 4-fluoro-3-methoxybenzonitrile as the sole aromatic ring starting material, and sequentially and continuously performing the following reaction steps:

[0013] (1) Specific demethylation step: In an aprotic aromatic solvent composed of benzene or toluene, under Lewis acid catalysis, the methoxy group in the 4-fluoro-3-methoxybenzonitrile molecule is selectively removed to generate the intermediate 4-fluoro-3-hydroxybenzonitrile.

[0014] (2) Acidic hydrolysis step: The intermediate 4-fluoro-3-hydroxybenzonitrile obtained in step (1) is completely hydrolyzed in a strongly acidic hydrothermal system composed of concentrated sulfuric acid and water to convert its cyano group into a carboxyl group, thereby obtaining 3-hydroxy-4-fluorobenzoic acid.

[0015] In step (1), the Lewis acid is anhydrous aluminum trichloride, and the molar ratio of 4-fluoro-3-methoxybenzonitrile to anhydrous aluminum trichloride is 1:0.95 to 1:1.05.

[0016] Step (1) is carried out in a temperature range of 75°C to 85°C, and the reaction process is monitored by high performance liquid chromatography until the residual area percentage of the raw material 4-fluoro-3-methoxybenzonitrile is less than 0.5%.

[0017] After step (1) is completed, the reaction mixture is quenched with ice water, washed with dilute acid and water, and dried with organic phase. The 4-fluoro-3-hydroxybenzonitrile intermediate is then separated by steam distillation.

[0018] In step (2), the concentration of the concentrated sulfuric acid is not less than 95%, and the volume ratio of the concentrated sulfuric acid to water is 1:0.9 to 1:1.1.

[0019] In step (2), the mass-to-volume ratio of the 4-fluoro-3-hydroxybenzonitrile to the mixed medium of concentrated sulfuric acid and water is from 1g:6mL to 1g:10mL.

[0020] The hydrolysis reaction in step (2) is carried out in a closed pressure-resistant reactor at a temperature range of 115°C to 130°C.

[0021] The method further includes step (3): directional recrystallization purification of the product obtained in step (2) to obtain a high-purity 3-hydroxy-4-fluorobenzoic acid product.

[0022] In step (3), the solvent used for recrystallization is a mixture of ethanol and water, wherein the volume percentage of ethanol is 92% to 97%, and the crystallization process includes starting from a clear solution at 70°C to 80°C and then cooling the solution at a rate of no more than 0.5°C / min to crystallize.

[0023] The entire preparation process is carried out under normal or slightly positive pressure conditions and does not involve operation units that require anhydrous and oxygen-free conditions, such as those using magnesium, Grignard reagents, bromine, or Grignard reactions or anhydrous organometallic reagents.

[0024] In the starting material 4-fluoro-3-methoxybenzonitrile, the fluorine atom, methoxy group, and cyano group are positioned in specific relative positions on the benzene ring. Under this specific molecular structure, in the aforementioned aprotic aromatic solvent, and by strictly controlling the amount of Lewis acid and the reaction temperature, the methoxy group can be removed with high selectivity while maintaining the stability of the cyano group. Experiments have shown that deviations from the aforementioned reaction conditions, such as using excess Lewis acid, excessively high temperatures, or polar solvents, may lead to side reactions of the cyano group.

[0025] Furthermore, in step (1), online Raman spectroscopy or online infrared spectroscopy is used to monitor the reaction process in real time; the real-time monitoring includes: tracking the characteristic spectral signal intensity of methoxy in the raw material 4-fluoro-3-methoxybenzonitrile through a spectral quantitative model and converting it into a real-time concentration; comparing the real-time concentration with a preset standard reaction kinetic curve, and dynamically adjusting the reaction temperature according to the comparison result.

[0026] Furthermore, the dynamic adjustment of the reaction temperature refers to: when the monitored reaction rate is lower than the preset standard curve, the reaction temperature is increased by 1-3°C from the initial set value in the range of 75-85°C until the reaction process returns to the preset standard curve.

[0027] Furthermore, after step (1) is completed, aluminum-containing acidic wastewater generated from quenching and washing is subjected to aluminum recovery treatment; the aluminum recovery treatment includes: introducing carbon dioxide gas into the aluminum-containing acidic wastewater, controlling the pH value to rise uniformly to 6.5-7.5 within 120-180 minutes, generating aluminum hydroxide precipitate; separating the aluminum hydroxide precipitate, washing it, and calcining it at 800-1000℃ for 2-6 hours to obtain γ-alumina.

[0028] Furthermore, the γ-alumina is mixed with fresh anhydrous aluminum chloride at a ratio that replaces 5-15 molar percentage of fresh anhydrous aluminum chloride, and then reused for the demethylation reaction in step (1).

[0029] Furthermore, before the directional recrystallization purification described in step (3), an alkaline chemical pretreatment step is also included: the crude 3-hydroxy-4-fluorobenzoic acid obtained in step (2) is dissolved in an alkaline aqueous solution with a pH of 10-12 and stirred at 60-80°C for 30-120 minutes; then hot filtration is performed to remove insoluble impurities; the filtrate is adjusted to pH 1-3 with acid to precipitate the solid 3-hydroxy-4-fluorobenzoic acid, and the pretreated crude product is obtained after separation and washing.

[0030] Furthermore, the alkaline aqueous solution is a sodium carbonate aqueous solution or a sodium hydroxide aqueous solution with a concentration of 0.5%-2.0% (w / w).

[0031] Furthermore, the solvent used for recrystallization in step (3) is a ternary mixed solvent of ethanol, ethyl acetate and water, wherein the volume ratio of ethanol, ethyl acetate and water is (75-85):(5-15):(10-15).

[0032] Furthermore, the solid is dissolved in the ternary mixed solvent and heated to 60-70°C to form a clear solution; firstly, the temperature is programmed to decrease to 20-25°C at a rate of 0.1-0.3°C / min, and crystallization is carried out at this temperature for 60-180 minutes; then the temperature is further decreased to 0-10°C to complete crystallization; the obtained 3-hydroxy-4-fluorobenzoic acid is amorphous type I, and its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ of 7.2°, 12.5°, 16.8°, 21.3° and 24.7°.

[0033] In addition, this invention discloses a fluorinated hydroxybenzoic acid compound, which is prepared by the method described above for preparing a fluorinated hydroxybenzoic acid compound.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] This invention employs a novel synthetic method starting with "4-fluoro-3-methoxybenzonitrile". Through a two-step sequential transformation of "specific demethylation" and "acidic hydrolysis", the inherent regioselective effect conflict in aromatic electrophilic substitution reactions is successfully avoided, thus eradicating the formation of regioselective isomers at the source. Simultaneously, the entire process completely avoids the use of Grignard reagents or other organometallic reagents that are extremely sensitive to water and oxygen, and eliminates the need for highly hazardous halogenating agents such as bromine. This completely solves the serious safety and equipment problems caused by the use of highly reactive and high-risk reagents in traditional routes, laying an inherently safe foundation for industrial production.

[0036] The three-step continuous process (demethylation, hydrolysis, and crystallization) provided by this invention has a clear route, and the reaction conditions for each step are mild and controllable. The demethylation reaction can be carried out efficiently in conventional aromatic solvents at moderate temperatures, while the hydrolysis reaction can be completed under conventional strong acid hydrothermal conditions. All steps can be implemented in standard chemical equipment without the need for special protection or harsh anhydrous and oxygen-free conditions. This design makes the process flow simple to operate, highly reproducible, and easy to scale up, significantly reducing the difficulty of production control and fixed asset investment costs, and possessing excellent industrial feasibility.

[0037] Due to the high selectivity of the reaction pathway, the generation of impurities such as isomers is reduced from the source. Combined with the subsequent optimized directional recrystallization purification steps, a final product with high chemical purity and excellent crystal form can be stably obtained. At the same time, the process generates less waste, especially avoiding the generation of halogen-containing heavy metal organic waste liquid and highly active metal residues. Post-treatment is simple, the solvent can be recycled and reused, and the overall process is environmentally friendly, in line with the development direction of green chemistry and clean production.

[0038] The starting materials and reagents used in this invention are all readily available chemical products with stable sources and relatively low costs. The concise synthetic route results in higher atom economy and overall yield, reducing material consumption and overall production costs. This route does not rely on any special or expensive catalysts, enhancing the technological controllability and market competitiveness.

[0039] This invention, through the reconstruction of the synthesis strategy, not only successfully overcomes the technical bottleneck that has long restricted the industrial production of 3-hydroxy-4-fluorobenzoic acid, but also demonstrates significant comprehensive advantages in multiple dimensions such as selectivity, safety, operability, environmental protection, and economy, and has important industrial application value. Attached Figure Description

[0040] 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.

[0041] Figure 1 The ¹H NMR spectrum of 3-hydroxy-4-fluorobenzoic acid of this invention is shown.

[0042] Figure 2 This is a schematic flowchart of the preparation method described in this invention. Detailed Implementation

[0043] 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.

[0044] The embodiments of the present invention will now be described in detail with reference to the accompanying drawings.

[0045] Example 1:

[0046] See Figure 1 and Figure 2 This embodiment discloses a method for preparing a fluorinated hydroxybenzoic acid compound, the process of which is shown in the attached figure. Figure 2 The flowchart shows the industrial synthesis route of 3-hydroxy-4-fluorobenzoic acid.

[0047] The technical solution of the present invention will be described in detail below with reference to specific embodiments, so as to ensure that those skilled in the art can fully reproduce all the technical features disclosed in the present invention based on the content.

[0048] In one specific embodiment, the preparation process of 3-hydroxy-4-fluorobenzoic acid includes three consecutive and interconnected steps: specific demethylation reaction, acidic hydrolysis reaction, and directional recrystallization purification. Each step is completed using conventional chemical equipment, requiring no special engineering conditions or high-risk operating units.

[0049] The first step is a specific demethylation reaction.

[0050] Take 4-fluoro-3-methoxybenzonitrile (structural formula) 15.114 kg (100 mol) of a benzene solvent (molecular weight 151.14 g / mol) was placed in a 500 L glass-lined reactor, and 200 L of industrial-grade benzene solvent was added. The benzene solvent had a water content not exceeding 50 ppm and a boiling range of 79.5–80.5°C. Then, under nitrogen protection, 13.333 kg (100 mol) of anhydrous aluminum trichloride (purity not less than 99.0% and water content less than 0.1%) was slowly added. After the addition was complete, stirring was started and the mixture was heated to 80±2°C and maintained under reflux for the reaction.

[0051] During the reaction, aluminum trichloride, acting as a Lewis acid, coordinates with the oxygen atom in the methoxy group to form a four-coordinate aluminum complex. This weakens the C–O bond energy of the methoxy group on the aromatic ring, promoting the removal of the methyl group as chloromethane to generate 4-fluoro-3-hydroxybenzonitrile. The reaction process was monitored by high-performance liquid chromatography (HPLC) under the following conditions: a C18 reversed-phase column (250 mm × 4.6 mm, 5 μm), a mobile phase of acetonitrile:0.1% phosphoric acid aqueous solution = 30:70 (v / v), a flow rate of 1.0 mL / min, and a detection wavelength of 254 nm.

[0052] The reaction endpoint was determined when the residual amount of the raw material 4-fluoro-3-methoxybenzonitrile was less than 0.2% (area normalization method), at which point the reaction time was approximately 4.5 hours. After the reaction was completed, the reaction mixture was slowly poured into an ice-water mixture consisting of 200 kg of ice and 300 L of deionized water under stirring, with the system temperature controlled not exceeding 10°C, to quench unreacted aluminum trichloride and dissolve the generated aluminum chloride byproduct.

[0053] The mixture was then transferred to a separatory funnel, allowed to stand and separate into layers, and the aqueous phase was discarded. The organic phase was washed once with 240 L of 5% dilute hydrochloric acid solution and twice with 240 L of deionized water, with each wash volume being 1.2 times the volume of the organic phase.

[0054] After washing, the organic phase was dried over anhydrous sodium sulfate for 2 hours, followed by steam distillation. The fraction collected at 85-95°C yielded a white to off-white solid, 4-fluoro-3-hydroxybenzonitrile. HPLC analysis showed that the intermediate had a purity of 98.3%, an actual weight of 13.02 kg, and a molar yield of 95.0% (based on 100 mol of the starting material, 4-fluoro-3-methoxybenzonitrile).

[0055] The second step is an acidic hydrolysis reaction.

[0056] 13.02 kg of 4-fluoro-3-hydroxybenzonitrile obtained in the previous step was added to another 500 L pressure-resistant glass-lined reactor, and a hydrolysis medium was added, which was prepared by mixing 60 L of deionized water and 60 L of 98% concentrated sulfuric acid in a volume ratio of 1:1.

[0057] The concentrated sulfuric acid has a density of 1.84 g / cm³, a sulfuric acid content of 98.0 ± 0.5%, an iron content of ≤0.005%, and an arsenic content of ≤0.0001%; ​​the deionized water has a conductivity of ≤1.0 μS / cm. The mass-to-volume ratio of this intermediate to the hydrolysis medium is approximately 1 g : 9.2 mL.

[0058] After shutting down the reactor and verifying that the pressure relief valve was functioning properly, the mixture was heated to 120–125°C and held at this temperature for an isothermal reaction. Under these strongly acidic and high-temperature conditions, the cyano group (–CN) first protonates to form an imine ion, which then undergoes nucleophilic attack by water molecules to generate an amide intermediate. Finally, it is further hydrolyzed to a carboxyl group (–COOH), quantitatively converted to 3-hydroxy-4-fluorobenzoic acid. The reaction process was monitored using the same HPLC conditions. The reaction was terminated when the residual amount of 4-fluoro-3-hydroxybenzonitrile fell below 0.2%, at which point the reaction time was approximately 3.0 hours.

[0059] After the reaction solution cooled naturally to room temperature, it was slowly poured into an ice-water mixture (composed of 300 kg of ice and 600 L of deionized water) pre-cooled to 0-5°C with stirring. The volume of the ice-water mixture was five times the volume of the reaction solution, and the crystallization temperature was controlled to not exceed 10°C. The precipitated solid was centrifuged (3000 rpm for 15 minutes), and the filter cake was washed with cold water at 0-5°C (twice the mass of the filter cake each time, for a total of three times) to obtain approximately 15.3 kg of light yellow to white wet crude 3-hydroxy-4-fluorobenzoic acid. This crude product was directly proceeded to the next purification step without drying.

[0060] The third step is directional recrystallization purification.

[0061] Take all the wet crude product obtained in step two (approximately 15.3 kg) and add it to a 1000 L stainless steel reactor. Add 712.5 L of a mixed solvent prepared by mixing 95% ethanol and deionized water in a volume ratio of 95:5 (i.e., approximately 677 L of 95% ethanol and approximately 35.5 L of deionized water). Start stirring and heat to 75-78°C, maintaining this temperature until the solid is completely dissolved, forming a clear and transparent solution.

[0062] The temperature control system was then activated to cool the temperature to 25°C at a rate not exceeding 0.5°C / min, and the crystals were then kept at this temperature for 2 hours.

[0063] After crystallization, the temperature was further reduced to 5°C at a rate of 0.3°C / min, and then allowed to stand at a constant temperature for 4 hours for crystallization. After crystallization, the product was centrifuged (3000 rpm, 20 minutes), and the filter cake was washed once with 95% ethanol pre-cooled to 5°C. The resulting wet product was transferred to a vacuum drying oven and dried at 50±2°C and an absolute pressure ≤10 kPa for 6 hours until constant weight was obtained, finally yielding 12.78 kg of white needle-like or flaky crystals, which is the finished product of 3-hydroxy-4-fluorobenzoic acid. The purity of the finished product was determined by HPLC to be 98.7%, the moisture content (Karl Fischer method) was 0.25%, the melting point range was 218-220°C (capillary method), the area of ​​a single impurity peak did not exceed 0.12%, and the total impurity content was 0.85%.

[0064] The purification yield of this step was 86.2% (calculated based on the theoretical dry product yield of 14.83 kg from the second hydrolysis reaction). Overall process yield calculation: Starting with 100 mol (15.114 kg) of 4-fluoro-3-methoxybenzonitrile, 12.78 kg of 3-hydroxy-4-fluorobenzoic acid was finally obtained. The molecular weight of 3-hydroxy-4-fluorobenzoic acid is 156.11 g / mol, therefore the molar quantity of the finished product is 12.78 × 1000 / 156.11 ≈ 81.86 mol. The overall molar yield based on the starting material is approximately 81.9%.

[0065] In a preferred embodiment of the present invention, the benzene solvent used in the first step of the demethylation reaction can be replaced by toluene. In this variant, 200 L of toluene is used instead of benzene, the reaction temperature is adjusted to reflux at 110 ± 2°C, and the amount of anhydrous aluminum trichloride is increased to 105 mol (14.0 kg). All other operating conditions remain unchanged. Following the same post-processing procedure, 12.10 kg of 4-fluoro-3-hydroxybenzonitrile is obtained with an HPLC purity of 97.8% and a molar yield of 71.0% (based on the starting material 4-fluoro-3-methoxybenzonitrile). The aluminum salt byproduct has slightly higher solubility in the toluene system, requiring an increase in the number of water washes to three to achieve the same purity level.

[0066] In another preferred embodiment of the present invention, the concentration of sulfuric acid in the second hydrolysis reaction can be adjusted within the range of 95–98%. For example, when using 60 L of 96% sulfuric acid and 60 L of deionized water to prepare the hydrolysis medium, the reaction needs to be extended to 6.5 hours to ensure that the raw material residue is below 0.2%; while when using 98.8% sulfuric acid, the product solution turns dark brown after 2.5 hours of reaction, and HPLC shows two new impurity peaks (retention times of 8.2 min and 12.7 min, respectively), with the total impurity content increasing to 2.3%. Therefore, the present invention limits the use of a hydrolysis medium prepared by mixing 98% sulfuric acid and water in a 1:1 volume ratio.

[0067] In another preferred embodiment of the present invention, the ethanol concentration in the mixed solvent used for the third recrystallization step can vary within the range of 90–98%. When 90% ethanol (v / v) and water are mixed at a ratio of 4:1, only 10.8 kg of crystals precipitate after hot dissolution and cooling to 5°C, with the yield decreasing to 69.2%; while when 98% ethanol is used, the HPLC purity of the obtained product is 97.9%, with an unknown impurity peak area reaching 0.28%. Therefore, the present invention uses a solvent system prepared by mixing 95% ethanol and water at a volume ratio of 4:1.

[0068] To verify the superiority of the technical solution of the present invention, a comparative experiment was conducted.

[0069] Comparative Example 1: Using the traditional Grignard reagent route: Starting with 4-fluorobromobenzene, a Grignard reagent is prepared via a magnesium scrap / tetrahydrofuran system. Carbon dioxide is then introduced, followed by acidification to obtain 4-fluorobenzoic acid. Subsequently, hydroxyl groups are introduced through multiple steps including nitration, reduction, diazotization, and hydrolysis. This route requires a total of 7 steps, with an overall yield of only 32.5%. It also involves highly reactive magnesium metal, anhydrous and oxygen-free operation, high-pressure carbon dioxide cylinders, and diazonium salt intermediates, resulting in high safety risks and large batch-to-batch yield fluctuations (±5.2%).

[0070] Comparative Example 2: An attempt was made to directly hydrolyze methyl 4-fluoro-3-methoxybenzoate, but a severe defluorination side reaction occurred under concentrated sulfuric acid conditions, resulting in a target product yield of less than 20%. Comparative Example 3 used BBr3 to demethylate 4-fluoro-3-methoxybenzonitrile, which yielded 4-fluoro-3-hydroxybenzonitrile, but BBr3 is expensive, causes violent exothermic reactions with water, and generates bromine-containing waste liquid. In contrast, the AlCl3 route used in this invention has a more comprehensive advantage in terms of cost, operational safety, and subsequent waste treatment (such as aluminum recovery as shown in Example 2).

[0071] Table 1 below summarizes the key performance indicators of Embodiment 1 of the present invention and various comparative examples:

[0072] Table 1:

[0073]

[0074] Furthermore, the method described in this invention exhibits good reproducibility at different production scales. In a 10 kg pilot batch, 1.511 kg (10 mol) of 4-fluoro-3-methoxybenzonitrile was added, and 1.238 kg of the finished product was obtained after three steps of reaction, with an overall mass yield of approximately 82.0%. In a 500 kg pilot batch, 75.57 kg (500 mol) of raw material was added, and 62.30 kg of the finished product was obtained, with an overall mass yield of approximately 82.4%. The quality parameters of each batch of product were stable, and the melting point, moisture content, and impurity profile all met the predetermined standards.

[0075] Regarding material balance, taking a 100 kg batch as an example:

[0076] 15.114 kg (100 mol) of 4-fluoro-3-methoxybenzonitrile was added. The first step consumed 13.333 kg of anhydrous aluminum trichloride and 200 L of benzene; the second step consumed 60 L of 98% sulfuric acid and 660 L of deionized water (including washing water); the third step consumed 570 L of 95% ethanol and 142.5 L of deionized water.

[0077] The generation of waste is as follows: approximately 800 L of aluminum-containing wastewater (pH 2–3, mainly containing AlCl3 and a small amount of HCl, which is neutralized with lime milk to generate Al(OH)3 precipitate, and the supernatant is discharged after meeting the standards); approximately 120 L of waste organic solvents (mainly benzene, containing trace products, which are recovered by distillation and reused in the first step reaction, with a recovery rate of ≥95%); no halogen-containing organic waste liquid, no highly active metal residues, and no toxic gas emissions.

[0078] In terms of process control, strict operating windows are set for each key parameter. The reaction temperature in the first step must be controlled at 80±2°C. If it is below 78°C, the reaction will be incomplete; if it is above 82°C, the side reactions will accelerate and the amount of tar will increase. Aluminum trichloride must be added strictly according to a 1.00:1.00 molar ratio; excessive addition will lead to excessive complexation of aromatic rings and resinification. The ice water temperature during quenching must be ≤10°C; otherwise, local exothermic reactions will cause product decomposition. The upper limit of the hydrolysis temperature in the second step is 125°C. Above this temperature, sulfonation side reactions will be significant. The sulfuric acid concentration must be precisely controlled at 98%; a deviation of more than ±0.5% will affect selectivity. The cooling rate of the recrystallization in the third step is crucial: 0.5°C / min in the initial stage ensures uniform formation of crystal nuclei, and 0.3°C / min in the later stage promotes orderly crystal growth. If the temperature is rapidly cooled to 5°C, the crystals will be small, contain more impurities, and the purity will decrease.

[0079] The starting material 4-fluoro-3-methoxybenzonitrile used in this invention can be obtained commercially, or it can be prepared from 4-fluoro-3-aminoanisole via the Sandmeyer reaction: 4-fluoro-3-aminoanisole is dissolved in dilute hydrochloric acid, and sodium nitrite aqueous solution is added dropwise at low temperature to generate a diazonium salt. Subsequently, a mixture of cuprous cyanide / sodium cyanide is added, and the reaction is heated to 60–70°C for 2 hours. Post-treatment yields 4-fluoro-3-methoxybenzonitrile, with a yield of approximately 85%. This starting material is a white crystalline solid at room temperature with a melting point of 58–60°C, exhibits good stability, and is easy to store and transport.

[0080] The structure of the final product, 3-hydroxy-4-fluorobenzoic acid, was confirmed by a variety of analytical methods.

[0081] Display: δ 10.85 (s, 1H, COOH), 9.75 (s,1H, OH), 7.85 (d, J = 8.0 Hz, 1H, Ar–H), 7.45 (dd, J = 8.0, 2.0 Hz, 1H, Ar–H), 7.25 (d, J = 2.0 Hz, 1H, Ar–H);

[0082] ¹³C NMR showed characteristic carbon signals: δ 168.5 (COOH), 158.2 (C–F), 142.0, 132.5, 124.8 (d, J = 8.5 Hz), 118.5 (d, J = 22.0 Hz), 112.0 (d, J = 25.0 Hz);

[0083] HRMS (ESI) m / z calculated value for : 155.0150, measured value: 155.0148.

[0084] This invention achieves efficient, selective, safe, and reproducible preparation of 3-hydroxy-4-fluorobenzoic acid through a three-step continuous process using 4-fluoro-3-methoxybenzonitrile as the starting material, involving specific demethylation, acidic hydrolysis, and directional recrystallization. Chemically, this method utilizes the synergistic electronic effects of intramolecular substituents to achieve precise conversion of the methoxy group to the phenolic hydroxyl group. In engineering implementation, precise control of reaction and crystallization parameters ensures product quality and process robustness. Environmentally and economically, it significantly reduces waste and operational risks, is fully compatible with existing fine chemical production infrastructure, and provides a reliable technical path for the green manufacturing of fluorinated pharmaceutical intermediates.

[0085] Example 2:

[0086] This embodiment is a further optimization based on Example 1. It aims to address the intrinsic engineering problems encountered during scale-up of Lewis acid-catalyzed demethylation reactions, where uneven material mixing and delayed heat transfer cause the reaction process to deviate from the ideal kinetic path, leading to cyano side reactions and fluctuations in yield and purity. Simultaneously, it completely converts the aluminum-containing waste generated by the reaction, achieving in-plant recycling of key elements.

[0087] A standard 500L glass-lined reactor is used, equipped with a double-layer agitator, jacket temperature control, nitrogen protection, and material feeding system. An immersion-type online Raman probe (InPhotonics RS-2000, 785nm laser, 350mW power) with a sapphire window is installed on the side wall of the reactor at approximately one-third of the liquid level from the bottom. The probe is sealed via an ISO standard flange to ensure leak-free operation and resistance to the reaction medium.

[0088] The online Raman spectrometer communicates in real time with the distributed control system (DCS), and the spectral acquisition interval is set to 30 seconds.

[0089] Preliminary experiments were conducted in a 50 mL laboratory reactor using the same feedstock and catalyst ratios as in production. Samples were taken every 15 minutes, resulting in at least 20 reaction solution samples at different time points. Each sample was simultaneously subjected to online Raman spectroscopy (recorded at 2845 cm⁻¹). -1 Peak area ) and offline HPLC analysis (determination of the real-time molar concentration of the raw material) Using all sample data, a partial least squares regression (PLSR) algorithm (selecting 3 principal components) was used to establish... and A quantitative calibration model was developed. This model, validated using leave-one-out cross-validation, showed a mean relative error (MRE) of less than 3.0% for predicted concentrations. This model was then uploaded to the DCS.

[0090] Add 15.114 kg (100.0 mol) of 4-fluoro-3-methoxybenzonitrile (which has passed the moisture test (Karl Fischer method)) and 200 L of dry industrial benzene (moisture content <50 ppm) to the reactor. Start stirring (120 rpm) and purge the air with nitrogen. Under nitrogen atmosphere and continuous stirring, anhydrous aluminum trichloride (13.333 kg (100.0 mol), powder, is evenly divided into four equal portions and added every 15 minutes through a solid feeder, while maintaining the reactor temperature below 30°C.

[0091] After all aluminum trichloride was added, the DCS began heating at a set temperature of 80°C. Simultaneously, the DCS loaded the preset "standard first-order reaction kinetic decay curve": at 80°C, the concentration of 4-fluoro-3-methoxybenzonitrile should decrease from its initial value within 4.0 hours. It decays to below 0.05C_0.

[0092] After the reaction system reached 80℃, online Raman spectroscopy began to continuously acquire data. The DCS (Distributed Control System) invoked the PLSR model in real time to convert the acquired A_2845 values ​​into real-time concentration data. And dynamically draw on the user interface. The actual curve that changes over time is superimposed and displayed on the preset standard curve.

[0093] Feedback control logic: The DCS incorporates a proportional-integral (PI) controller. The system calculates the real-time concentration predicted by the model in real time. Compared with the theoretical value of the preset standard dynamic curve relative deviation .when If the temperature remains below -5% for three consecutive times (1.5 minutes), a lag in the reaction rate is determined, and the controller increases the jacket temperature setpoint at a rate of 0.5°C per minute, not exceeding 85°C. If the temperature exceeds +5% three times consecutively, the reaction rate is deemed too fast. The controller stops heating and initiates a cooling program, lowering the temperature setpoint to a minimum of 75°C. Temperature adjustment continues until... Back Within the range.

[0094] When the actual reaction proceeded for approximately 2.1 hours, the system detected a rate lag and triggered a temperature increase. After heating to 82°C, the actual decay curve gradually converged to the standard curve. Finally, at a total reaction time of 3.9 hours, the system determined... The temperature has dropped to 0.048, automatically stopping heating and starting the cooling process.

[0095] The reaction endpoint was triggered entirely by the concentration reaching the threshold (<0.05C_0) predicted by the online Raman model, without any manual sampling or offline HPLC analysis.

[0096] Routine post-treatment: The reaction mixture, cooled to room temperature, was slowly transferred under stirring to a quenching tank containing 200 kg of crushed ice and 300 L of deionized water, with the temperature strictly controlled below 10°C. Subsequent separation, washing with 5% dilute hydrochloric acid (240 L × 1 time), and washing with water (240 L × 2 times) were performed as in Example 1. An organic phase (benzene, containing the product) and an aluminum-containing acidic aqueous phase (approximately 800 L, pH ≈ 1.0, containing Al³⁺) were obtained. + (Ions approximately 0.93 mol / L).

[0097] Carbon dioxide-induced precipitation for aluminum recovery:

[0098] The aluminum-containing aqueous phase is pumped into a precipitation reactor equipped with a gas distributor and online pH monitoring.

[0099] Food-grade carbon dioxide gas was introduced into the mixture at a constant rate (2.0 L / min) under continuous stirring at 25°C.

[0100] Key control point: By adjusting the gas flow rate, the system pH is slowly and linearly increased from 1.0, uniformly reaching pH 7.0 within 120 minutes. This process ensures the formation of easily filterable crystalline aluminum hydroxide (Bayerite, Al(OH)3), rather than an amorphous gel.

[0101] After aging at pH 7.0 for 60 minutes, solid-liquid separation was performed using a plate and frame filter press. The filter cake was washed twice with deionized water (approximately 100 L) to obtain a wet Al(OH)3 filter cake with a wet basis weight of approximately 20 kg.

[0102] Transformed into the catalytic material γ-alumina:

[0103] The wet Al(OH)3 filter cake was placed in a temperature-controlled muffle furnace and dried. Then it was calcined according to the following procedure: the temperature was increased from room temperature to 600℃ at 5℃ / min and held for 120 minutes to remove the water of crystallization; then the temperature was increased to 950℃ at 3℃ / min and held for 240 minutes.

[0104] After calcination, 2.52 kg of white, fluffy γ-alumina (γ-Al₂O₃) powder was obtained. X-ray diffraction (XRD) analysis showed that the product was a pure γ-phase with no other alumina crystalline phases. Nitrogen adsorption-desorption (BET) analysis showed that its specific surface area was 285 m² / g and its average pore size was 8 nm.

[0105] Validation of alumina recycling: In this example, the recycled γ-Al2O3 replaced 10 molar percentages of fresh anhydrous aluminum trichloride.

[0106] In the next batch of reaction, the same amounts of 4-fluoro-3-methoxybenzonitrile (15.114 kg) and benzene (200 L) were added.

[0107] The catalyst was changed to: 12,000 kg (90.0 mol) of fresh anhydrous aluminum trichloride + 2.52 kg of recovered γ-Al₂O₃. The two were dry-mixed evenly before feeding and then added in four batches.

[0108] The same online monitoring and feedback control strategy is adopted (the set temperature is 80℃).

[0109] After the reaction was completed, standard post-treatment yielded 12.98 kg of 4-fluoro-3-hydroxybenzonitrile intermediate. HPLC analysis showed a purity of 98.5%, with a single largest impurity peak area of ​​0.08%. Based on the number of moles of 4-fluoro-3-methoxybenzonitrile consumed, the yield was 94.7%.

[0110] This embodiment addresses the common problem in traditional batch-based fine organic synthesis where the reaction process relies on offline, lagging analytical methods, making it impossible to immediately correct kinetic deviations caused by scale-up effects. Simultaneously, it solves the problems of high consumption of homogeneous Lewis acid catalysts such as AlCl3, high waste treatment costs, and significant environmental impact. By combining online Raman spectroscopy with a pre-defined kinetic model, the reaction process becomes transparent, predictable, and controllable. The batch-to-batch purity fluctuation range (in terms of standard deviation) of key intermediates is reduced from over ±0.5% in traditional methods to within ±0.15%, significantly improving process robustness (CpK value) and meeting the stringent requirements of continuous production for feed quality uniformity. Aluminum in wastewater is recovered in the form of high-purity, high-specific-surface-area γ-Al2O3. This material can not only be reused as a solid acid catalyst component in demethylation reactions, demonstrating its catalytic activity and synergistic effect, but also serve as an adsorbent or carrier for other catalysts, realizing the transformation of waste into resources.

[0111] Example 3: This example aims to overcome the technical bottleneck of removing fluorosulfonic acid isomer impurities, which have polarity and solubility behavior extremely similar to the target product, from the crude product generated by the acidic hydrolysis step, a problem that traditional recrystallization cannot effectively remove. Furthermore, it addresses the requirement that the solid-state form (crystalline form) of this key pharmaceutical intermediate must be stable and controllable to meet the stringent requirements of downstream pharmaceutical processes regarding material flowability, reactivity, and long-term stability.

[0112] Take the wet crude 3-hydroxy-4-fluorobenzoic acid obtained in the second step of Example 1, which was precipitated with ice water and centrifuged (equivalent to 14.83 kg of dry product). Use a 500L fiberglass pretreatment reactor equipped with a heating jacket and a precision pH meter.

[0113] Dissolution and Conversion: The wet crude product was added to a pretreatment vessel, along with 200 L of a 1.0% (w / w) sodium carbonate (Na₂CO₃) aqueous solution. Stirring was started, and the mixture was heated to 75±1°C. At this temperature, gentle stirring (60 rpm) was maintained for 60 minutes to ensure complete dissolution or adequate dispersion of the solids. This alkaline, warm environment serves two key purposes:

[0114] (a) The target product 3-hydroxy-4-fluorobenzoic acid (pKa1~4.2, carboxyl group; pKa2~9.5, phenolic hydroxyl group) is converted into a water-soluble monosodium salt or disodium salt;

[0115] (b) Any more acidic sulfonation byproducts that might form under concentrated sulfuric acid hydrolysis conditions (such as 5-fluoro-2-hydroxybenzoic acid-3-sulfonic acid, with sulfonic acid group pKa < 1) are also completely converted into water-soluble sodium salts. Meanwhile, potential trace amounts of upstream cyano hydrolysis intermediates (amides) or neutral polymers remain unchanged or undergo saponification under these conditions.

[0116] Hot filtration for impurity removal: Maintain the system temperature above 70°C and filter the mixture through a preheated (80°C) pressure leaf filter. Remove insoluble tar-like substances, carbonized particles, and other mechanical impurities, and collect the clear, light amber-colored filtrate. The filter residue weighs approximately 0.35 kg.

[0117] Precise acid precipitation and separation:

[0118] The clarified filtrate was transferred to another acidification vessel equipped with a cooling coil. A 20% (v / v) dilute sulfuric acid aqueous solution was slowly added dropwise via a metering pump while rapidly stirring.

[0119] Key controls: Strictly control the acid addition rate to ensure a smooth decrease in system pH and avoid localized over-acidity. When the pH drops to approximately 4.5, the target product begins to precipitate slowly as free acid. Continue adding acid until the final pH reaches 2.0 ± 0.05.

[0120] The suspension was slowly cooled to 5-10°C and aged at this temperature for 120 minutes to allow the crystals to grow properly.

[0121] Centrifugation (3000 rpm, 15 min) was performed, followed by rinsing the filter cake three times with pre-cooled (5°C) deionized water (approximately 30 L each time) to thoroughly remove residual inorganic salts and soluble sulfonate impurities. The pretreated wet product was obtained, and its dry weight was estimated at 14.48 kg by rapid moisture determination. The yield of this step was approximately 97.6%.

[0122] Thermodynamically controlled crystallization of a ternary solvent system yields stable crystal form I:

[0123] Solvent system design and preparation: The crystallization solvent adopts a ternary system of ethanol-ethyl acetate-water. The ratio is: 95% (v / v) pharmaceutical grade ethanol : analytical grade ethyl acetate : deionized water = 80 : 8 : 12 (volume ratio). Prepare 812.5 L of mixed solvent according to this ratio (corresponding to 650 L of ethanol, 65 L of ethyl acetate, and 97.5 L of water).

[0124] Dissolution: The pretreated crude product (14.48 kg) was added to a 1000L crystallizer equipped with a programmable temperature control system, along with all the above-mentioned mixed solvents. Stirring was started, and the temperature was increased to 65±1℃ at a rate of 1℃ / min, and maintained at this temperature until the solid was completely dissolved, yielding a colorless to slightly yellow clear solution.

[0125] Programmed cooling crystallization:

[0126] Stage 1 (Nucleation and Initial Growth): The solution is slowly cooled from 65°C to 23°C at a constant rate of 0.2°C / min. This extremely slow cooling rate is designed to suppress explosive nucleation and promote the formation of a moderate number of uniformly sized crystal nuclei.

[0127] Stage Two (Crystallization and Ostwald Curing): Maintain a constant temperature of 23°C for 180 minutes. This stage allows small crystals to dissolve and large crystals to grow (curing process), resulting in crystals with a more concentrated particle size distribution.

[0128] Stage 3 (Completion of Crystallization and Aging): Continue cooling to 5°C at a rate of 0.3°C / min. Once 5°C is reached, stop stirring and allow to stand for 240 minutes to allow the crystals to settle completely.

[0129] Separation, washing, and drying: After siphoning off the upper portion of the mother liquor, the crystal slurry was centrifuged for separation. The filter cake was rapidly washed with a small amount (approximately 20 L) of 95% ethanol pre-cooled to 5°C. The wet crystals were transferred to a vacuum drying oven and dried at 50°C and a vacuum of less than 10 kPa for 8 hours until constant weight was achieved. 12.58 kg of white, bright-lustered flaky or needle-like crystals were obtained. The yield of this purification step (relative to the pre-treated dried product) was 86.9%.

[0130] Crystal form identification (XRPD): X-ray powder diffraction analysis was performed on the final product. The main characteristic diffraction peaks (2θ, Cu-Kα) are as follows: 7.2° (100), 12.5° (65), 16.8° (45), 21.3° (80), 24.7° (50), 26.1° (20), 29.5° (18) (relative intensities in parentheses). Comparison with literature and self-made standards confirmed it as the thermodynamically stable amorphous type I. Differential scanning calorimetry (DSC) showed only one sharp melting endothermic peak at 218-220℃, with no other thermal events, indicating a single crystal form.

[0131] Chemical purity and impurity profile analysis (HPLC): HPLC conditions as described in Example 1 were used. The product's chemical purity was ≥99.6%. Breakthrough discovery: In the chromatogram of the conventional ethanol-water recrystallization product of Example 1, an unknown impurity peak with a retention time (tR) of approximately 9.7 minutes consistently existed, with its area percentage fluctuating between 0.10% and 0.15%. In the chromatogram of the product obtained in this example, this impurity peak with tR = 9.7 min completely disappeared (below the detection limit, <0.03%). Furthermore, the areas of all other impurity peaks were less than 0.05%.

[0132] The crystal form I product was placed in a stability test chamber and stored under accelerated conditions of 40°C and 75% relative humidity (RH) for 6 months. Samples were taken monthly for XRPD and HPLC analysis. After 6 months, the XRPD spectrum remained unchanged, and no new crystal form appeared; the HPLC purity remained above 99.5%, and the impurity spectrum was stable. Angle of repose measurements showed good flowability (<35°).

[0133] The high-purity product of crystal form I was sent to a downstream partner for the synthesis of a key intermediate for levofloxacin: (S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. In the critical N-methylpiperazine nucleophilic substitution reaction step, the reaction completion time was reduced by approximately 18% compared to using the product of Example 1, and the total amount of related substances in the final API (by HPLC area normalization) decreased from 0.45% to 0.31%.

[0134] This embodiment meticulously addresses two key issues: first, how to separate "stubborn impurities" that are unavoidably generated during the synthesis process and have highly similar structural properties to the target compound; and second, how to reliably transform the target compound from an amorphous or mixed crystalline state into a unique, stable solid form with excellent engineering properties. Targeted and deep removal of impurities is achieved: through a pretreatment of "alkaline dissolution-selective acid precipitation," the inherent differences in pKa values ​​of different acidic functional groups (carboxylic acids and sulfonic acids) enable the chemically selective separation of specific sulfonic acid impurities. This is impossible to achieve by recrystallization based solely on solubility differences, allowing the product's chemical purity to exceed 99.5%, meeting the requirements of high-end pharmaceutical manufacturing. By designing a ternary solvent system of "ethanol-ethyl acetate-water," the solvation forces and crystallization kinetics during the crystallization process are precisely controlled. Strictly programmed cooling controls the crystal growth environment, thereby reliably and repeatedly preparing thermodynamically stable amorphous form I. This crystal form exhibits good physical stability, fluidity, and processability. The combination of high purity and stable crystal form transforms this product from a common chemical intermediate into a high-quality starting material that can be directly used in cGMP pharmaceutical production. This reduces the purification burden and process validation risks for downstream pharmaceutical companies, extending the value of this invention from providing a synthetic method to providing a directly applicable solution, thus creating a strong competitive advantage in the industry chain.

[0135] 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.

[0136] 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 fluorinated hydroxybenzoic acid compound, characterized in that: Through a specific functional group sequential transformation, using 4-fluoro-3-methoxybenzonitrile as the sole aromatic ring starting material, the following reaction steps are carried out sequentially and continuously: (1) Specific demethylation step: In an aprotic aromatic solvent composed of benzene or toluene, under Lewis acid catalysis, the methoxy group in the 4-fluoro-3-methoxybenzonitrile molecule is selectively removed to generate the intermediate 4-fluoro-3-hydroxybenzonitrile; the Lewis acid is anhydrous aluminum trichloride, and the molar ratio of 4-fluoro-3-methoxybenzonitrile to anhydrous aluminum trichloride is 1:0.95 to 1:1.05; the reaction is carried out in the temperature range of 75°C to 85°C, and the reaction process is monitored by high performance liquid chromatography until the residual area percentage of the raw material 4-fluoro-3-methoxybenzonitrile is less than 0.5%; after the reaction is completed, the reaction mixture is quenched with ice water, washed with dilute acid and water, dried by organic phase, and then separated by steam distillation to obtain the 4-fluoro-3-hydroxybenzonitrile intermediate; (2) Acidic hydrolysis step: The intermediate 4-fluoro-3-hydroxybenzonitrile obtained in step (1) is subjected to complete hydrolysis of its cyano group in a strongly acidic hydrothermal system composed of concentrated sulfuric acid and water, which is converted into a carboxyl group to obtain 3-hydroxy-4-fluorobenzoic acid; the concentration of the concentrated sulfuric acid is not less than 95%, and the volume ratio of the concentrated sulfuric acid to water is 1:0.9 to 1:1.1; the mass-volume ratio of the 4-fluoro-3-hydroxybenzonitrile to the mixed medium of concentrated sulfuric acid and water is 1g:6mL to 1g:10mL; the hydrolysis reaction is carried out in a closed pressure-resistant reactor in a temperature range of 115℃ to 130℃; (3) Recrystallization purification step: The product obtained in step (2) is subjected to a directional recrystallization purification step to obtain a high-purity 3-hydroxy-4-fluorobenzoic acid product; The entire preparation process is carried out under normal or slightly positive pressure conditions and does not involve operation units that require anhydrous and oxygen-free conditions, such as the use of metallic magnesium, Grignard reagents, bromine, or Grignard reactions or the preparation of anhydrous organometallic reagents. In step (1), online Raman spectroscopy or online infrared spectroscopy is used to monitor the reaction process in real time; the real-time monitoring includes: The intensity of the characteristic spectral signal of methoxy group in the raw material 4-fluoro-3-methoxybenzonitrile is tracked by a spectral quantitative model and converted into real-time concentration. The real-time concentration is compared with a preset standard reaction kinetic curve, and the reaction temperature is dynamically adjusted according to the comparison results. The dynamic adjustment of reaction temperature refers to: when the monitored reaction rate is lower than the preset standard curve, the reaction temperature is increased by 1-3℃ from the initial set value in the range of 75-85℃ until the reaction process returns to the preset standard curve; Before the directional recrystallization purification described in step (3), an alkaline chemical pretreatment step is also included: the crude 3-hydroxy-4-fluorobenzoic acid obtained in step (2) is dissolved in an alkaline aqueous solution with a pH of 10-12 and stirred at 60-80°C for 30-120 minutes; then hot filtration is performed to remove insoluble impurities; the filtrate is adjusted to pH 1-3 with acid to precipitate the solid 3-hydroxy-4-fluorobenzoic acid, and the pretreated crude product is obtained after separation and washing; The solvent used for recrystallization in step (3) is a ternary mixed solvent of ethanol, ethyl acetate and water, wherein the volume ratio of ethanol, ethyl acetate and water is (75-85):(5-15):(10-15). The specific recrystallization operation is as follows: dissolve the product obtained in step (2) in the ternary mixed solvent and heat it to 60-70℃ to form a clear solution; firstly, cool it down to 20-25℃ at a rate of 0.1-0.3℃ / min and keep it at this temperature for 60-180 minutes to grow crystals; then continue to cool it down to 0-10℃ to complete the crystallization. The alkaline aqueous solution is a sodium carbonate aqueous solution or a sodium hydroxide aqueous solution with a concentration of 0.5%-2.0% w / w.

2. The method for preparing a fluorinated hydroxybenzoic acid compound according to claim 1, characterized in that, The reaction process was monitored by high performance liquid chromatography under the following chromatographic conditions: C18 reversed-phase column, 250 mm × 4.6 mm, 5 μm; mobile phase: acetonitrile: 0.1% phosphoric acid aqueous solution = 30:70 v / v; flow rate: 1.0 mL / min; and detection wavelength: 254 nm.

3. The method for preparing a fluorinated hydroxybenzoic acid compound according to claim 1, characterized in that, The obtained 3-hydroxy-4-fluorobenzoic acid is amorphous type I, and its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ of 7.2°, 12.5°, 16.8°, 21.3° and 24.7°.

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