2-fluoroacrylic acid preparation process based on selective dehydrofluorination

Abstract

The invention relates to the technical field of synthesis of fine chemicals for biological medicines, and discloses a selective dehydrofluorination-based 2-fluoroacrylic acid preparation process, which is characterized in that 1, 1-difluoro-2-hydracrylic acid ester as shown in a formula (I) is used as a raw material to prepare 2-fluoroacrylic acid through selective dehydrofluorination reaction under the action of a special composite catalyst, the process comprises the following steps: in the formula (I), CHF2CH (OH) COOR, wherein R is C1-C4 alkyl; the method comprises the following steps: (1) raw material pretreatment: purifying a 1, 1-difluoro-2-hydroxypropionate raw material, and controlling the content of metal impurities in the raw material to be less than or equal to 1ppm and the content of organic impurities to be less than or equal to 0.1%, so that the raw material meets the requirements of subsequent high-selectivity reaction; according to the present invention, the special composite catalyst is prepared by using the Al2O3-ZrO2 composite oxide with the specific composition as the carrier and modifying with the triethanolamine organic amine, such that the selective removal of the specific fluorine atom in the 1, 1-difluoro-2-hydroxypropionate molecule can be accurately promoted by the catalyst so as to effectively inhibit the occurrence of the competitive side reactions such as excessive defluorination, intramolecular dehydration, polymerization and the like.

Description

Technical Field

[0001] This invention relates to the field of fine chemical synthesis technology for biomedicine, specifically to a process for preparing 2-fluoroacrylic acid based on selective defluorination of hydrogen. Background Technology

[0002] 2-Fluoroacrylate, as an important fluorine-containing fine chemical, has broad application prospects in the biopharmaceutical field. In particular, it has shown great value in the synthesis of certain drug intermediates with special biological activities and as a key raw material for vaccine adjuvants. Pharmaceutical-grade 2-fluoroacrylate has extremely stringent requirements for purity, impurity content (especially fluoride ion residue), and batch consistency. It must comply with relevant pharmaceutical raw material standards such as the Pharmacopoeia of the People's Republic of China to ensure the safety and efficacy of the final drug.

[0003] Currently, the main methods for preparing 2-fluoroacrylic acid include direct fluorination of fluoroacrylic acid, hydrolysis of fluoroacrylates, and dehydrohalogenation of fluorinated precursors. Among these, the dehydrofluorination reaction from 1,1-difluoro-2-hydroxypropionate is theoretically an atom-economical route. However, this process faces two prominent technical challenges when moving towards pharmaceutical-grade product manufacturing: First, there is the challenge of selective control of the defluorination reaction. The 1,1-difluoro-2-hydroxypropionate molecule contains multiple reactive sites, and under the action of conventional acid-base catalysts, it is very easy to undergo non-selective defluorination, leading to multiple side reactions such as over-defluorination, intramolecular dehydration, and polymerization. This not only reduces the yield of the target product, but also introduces complex and difficult-to-remove organic impurities, which seriously affects the purity of the product and cannot meet the stringent limits on the content of single impurities in pharmaceutical raw materials (usually requiring ≤0.1% or even lower).

[0004] Secondly, there is the challenge of deep removal of impurities (especially fluoride ions) from pharmaceutical-grade products. As a key raw material in the synthesis of fluorine-containing compounds, trace amounts of residual fluoride ions in 2-fluoroacrylic acid may catalyze subsequent reactions, affect drug stability, and even bring potential biotoxicity. Existing processes often focus on the conversion and purification of the main reaction, paying insufficient attention to the deep removal of inorganic impurities such as fluoride ions. The lack of systematic process control and precise analytical detection methods results in large fluctuations in the residual fluoride ion content of the final product, making it difficult to consistently meet the pharmaceutical-grade standard of less than 1 ppm, let alone meet the requirements of ultra-low fluoride ion residue (usually ≤0.5 ppm) for high-end vaccine adjuvant raw materials. Summary of the Invention

[0005] The purpose of this invention is to provide a process for preparing 2-fluoroacrylic acid based on selective defluorination of hydrogen, so as to solve the problems mentioned in the background art.

[0006] To achieve the above objectives, the present invention provides the following technical solution: a 2-fluoroacrylic acid preparation process based on selective defluorination, using 1,1-difluoro-2-hydroxypropionate as shown in formula (I) as raw material, to prepare 2-fluoroacrylic acid through selective defluorination reaction under the action of a special composite catalyst, the process comprising the following steps: Formula (I): CHF2CH(OH)COOR, where R is a C1-C4 alkyl group; (1) Raw material pretreatment: The 1,1-difluoro-2-hydroxypropionate raw material is purified to control the content of metal impurities in the raw material to ≤1ppm and the content of organic impurities to ≤0.1%, so that the raw material meets the requirements of subsequent high-selectivity reaction; (2) Selective defluorination reaction: Pretreated 1,1-difluoro-2-hydroxypropionate is pumped into the reaction system at a feed rate of 0.1–0.5 mL / min, while an inert diluent is introduced simultaneously. The volumetric flow rate of the inert diluent is controlled at 0.5–2 L / h to ensure thorough mixing of the liquid feedstock and the inert diluent before entering the reactor. Subsequently, the mixture is introduced into a fixed-bed reactor packed with a special composite catalyst. The selective defluorination reaction is carried out at a reaction temperature of 80–120 °C and a reaction pressure of 0.1–0.3 MPa for 1–3 h. The special composite catalyst is composed of a metal oxide support and an organic amine modified component in a mass ratio of 8:2–9:1, wherein the metal oxide support is an Al2O3-ZrO2 composite oxide, and the organic amine modified component is triethanolamine; and the specific surface area of ​​the special composite catalyst is 150–250 m². 2 / g, with a pore size of 2-5nm; (3) Product purification: After the reaction product is condensed and collected, it is subjected to vacuum distillation, water washing to remove impurities and vacuum drying in sequence to obtain high-purity 2-fluoroacrylic acid; (4) Product quality control: The refined 2-fluoroacrylic acid is tested to ensure that the product purity is ≥99.8%, the content of a single impurity is ≤0.05%, and the residual amount of fluoride ions is ≤0.5ppm.

[0007] As a preferred technical solution of the present invention, the raw material purification in step (1) adopts molecular distillation, with a distillation temperature of 60-80℃ and a vacuum degree of ≤50Pa.

[0008] As a preferred technical solution of the present invention, the inert diluent in step (2) is one or a mixture of nitrogen and argon.

[0009] As a preferred embodiment of the present invention, the preparation method of the special composite catalyst in step (2) is as follows: Al2O3 and ZrO2 are mixed in a molar ratio of 3:1 to 5:1, deionized water is added and stirred into a slurry, aged at 40 to 60°C for 12 to 24 hours, and then calcined at 500 to 600°C for 3 to 5 hours to obtain Al2O3-ZrO2 composite oxide; after cooling the composite oxide to room temperature, it is immersed in a 5% to 15% triethanolamine aqueous solution and ultrasonically impregnated for 2 to 4 hours, wherein the liquid-to-solid ratio of the ultrasonic impregnation is 5:1 to 5:1. 10:1 (mL / g); then centrifuged and dried at 100-120℃ for 4-6 h to obtain a special composite catalyst; the triethanolamine is loaded on the support by forming hydrogen bonds and weak coordination with the hydroxyl groups on the surface of Al2O3-ZrO2 support. The hydroxyl and tertiary amine groups in its molecule synergistically regulate the density and intensity of Lewis acid / Brønsted base sites on the catalyst surface, thereby preferentially activating the fluorine atom in the CF bond at the β position with the hydroxyl group, promoting its removal in the form of HF, while inhibiting α-fluorine removal and intramolecular dehydration side reactions.

[0010] As a preferred technical solution of the present invention, the conditions for vacuum distillation in step (3) are: distillation temperature 70~90℃, vacuum degree ≤100Pa, and reflux ratio 1:2~1:5.

[0011] As a preferred technical solution of the present invention, in step (3), deionized water is used for water washing to remove impurities. The water washing temperature is 20-30°C, and the number of water washings is 2-3 times. The mass ratio of water to reaction product is 1:1 to 1:2 for each water washing.

[0012] As a preferred technical solution of the present invention, the vacuum drying conditions in step (3) are: drying temperature 40~60℃, vacuum degree ≤50Pa, and drying time 2~4h.

[0013] As a preferred technical solution of the present invention, the impurity detection in step (4) adopts a combination of high performance liquid chromatography (HPLC) and ion chromatography. The detection conditions of HPLC are as follows: the chromatographic column is a C18 column with a specification of 4.6 mm × 250 mm and a particle size of 5 μm; the column temperature is 30 °C; the mobile phase is methanol-water with a volume ratio of 30:70; the flow rate is 0.8–1.2 mL / min; the detection wavelength is 210 nm; and the injection volume is 10 μL. Ion chromatography is used to detect residual fluoride ions. The detection conditions are as follows: the chromatographic column is an anion exchange column with a specification of 4.0 mm × 250 mm; the column temperature is 30 °C; the mobile phase is 2.2 mmol / L sodium bicarbonate-1.8 mmol / L sodium carbonate buffer solution; the flow rate is 1.0 mL / min; and the detector is a conductivity detector. Quantitative analysis is performed using the external standard method during the detection process.

[0014] As a preferred embodiment of the present invention, in step (2), the fixed-bed reactor is a multi-stage gradient temperature-controlled reactor. The reactor is divided into a preheating section, a reaction section, and a stabilization section along the material flow direction. The temperature of the preheating section is 60–80°C, the temperature of the reaction section is 80–120°C, and the temperature of the stabilization section is 70–90°C. The temperature of each section is independently controlled, and the temperature difference control accuracy is ±2°C. The special composite catalyst loaded in the reaction section is loaded in a layered manner. The particle size of the catalyst decreases from 1.0 mm to 0.5 mm along the material flow direction, and the loading density is 0.8–1.2 g / cm³. 3 The bed pressure drop is ≤0.05MPa.

[0015] As a preferred technical solution of the present invention, the preparation process further includes step (5) regeneration and recycling of the catalyst: after the reaction is completed, an ozone-nitrogen mixture prepared on-site by an ozone generator is used, wherein the volume fraction of ozone in the mixture is controlled at 5-10%, and the deactivated catalyst is regenerated in situ at 150-200°C for 2-4 hours; during the regeneration process, an ozone concentration high limit alarm (>12%) and an automatic nitrogen purging interlock device are set to ensure safe operation; after the regenerated catalyst is purged with nitrogen and cooled to the reaction temperature, it is directly put into the next batch of reaction, and the number of cycles is ≥10 times. After a single cycle, the yield of 2-fluoroacrylic acid decreases by ≤1.5%, and the purity of the product still meets the product quality control requirements of step (4).

[0016] Compared with the prior art, the beneficial effects of the present invention are: 1. A specialized composite catalyst, prepared by using a specific Al2O3-ZrO2 composite oxide as a support and modifying it with triethanolamine organic amine, can precisely promote the selective removal of specific fluorine atoms in 1,1-difluoro-2-hydroxypropionate molecules. This catalyst effectively inhibits the occurrence of competitive side reactions such as excessive defluorination, intramolecular dehydration, and polymerization. Combined with optimized multi-stage gradient temperature-controlled reactors and process conditions, the reaction process is stable and controllable, maximizing the selective formation of 2-fluoroacrylic acid. This reduces the types and quantities of by-products from the source, providing a fundamental guarantee for the high purity and high yield of the target product.

[0017] 2. The process of this invention is not an improvement on a single reaction step, but rather a closed-loop quality control system that encompasses the entire process from "deep purification of raw materials - highly selective reaction - multi-stage refining and purification - compliant and precise detection." Raw material pretreatment controls metal and organic impurities at the source; a unique catalyst and reactor design reduces the generation of impurities during the reaction process; a multi-step refining combination of vacuum distillation, water washing, and vacuum drying effectively separates and removes various impurities; finally, a combination of high-performance liquid chromatography and ion chromatography is used for compliance detection, particularly for precisely monitoring fluoride ion residues, which are crucial for drug safety. This system ensures that the final 2-fluoroacrylic acid product consistently meets or even exceeds the stringent requirements of the Pharmacopoeia of the People's Republic of China for pharmaceutical raw materials in terms of purity, individual impurity content, and fluoride ion residues. It can be directly used for the synthesis of drug intermediates or the preparation of vaccine adjuvants, which are extremely sensitive to raw material quality.

[0018] 3. The special composite catalyst used in this invention can be efficiently regenerated in situ and reused multiple times through a specific ozone-nitrogen regeneration process. While maintaining high catalytic performance, it significantly reduces catalyst consumption costs and solid waste generation, which is in line with the concept of green chemistry and sustainable development. The combination of fixed-bed continuous reaction mode and catalyst regeneration technology makes the entire process easy to achieve large-scale, continuous and automated production, improves production efficiency and batch consistency, and provides reliable technical support for the stable and large-scale supply of pharmaceutical-grade 2-fluoroacrylic acid.

[0019] 4. From the initial process design stage, this invention targets the stringent quality requirements of the biopharmaceutical field. Through meticulous control of the entire process, the prepared 2-fluoroacrylic acid is no longer an ordinary chemical intermediate, but a "pharmaceutical grade" raw material that meets strict international and domestic pharmaceutical regulatory standards. This directly binds its application fields to high-end biopharmaceutical industries such as higher value-added drug intermediates (such as antiviral and antitumor drug synthesis) and new vaccine adjuvant raw materials, broadening the application prospects and significantly enhancing the market value and technological competitiveness of the product. Attached Figure Description

[0020] Figure 1 This is an overall flow chart of the preparation process of 2-fluoroacrylic acid based on selective defluorination of hydrogen, as described in this invention. Detailed Implementation

[0021] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0022] Example 1: Preparation of 2-fluoroacrylic acid based on selective defluorination Step (1) Raw material pretreatment Using industrial-grade methyl 1,1-difluoro-2-hydroxypropionate (CHF2CH(OH)COOCH3, R=CH3) as raw material, the initial metal impurity content was 5 ppm and the organic impurity content was 0.5%. Purification was carried out using a molecular distillation apparatus (model: KDZ-5, Shanghai Keyi), with the distillation temperature set at 70℃ and the system vacuum at 40 Pa. After distillation, samples were taken and determined by inductively coupled plasma mass spectrometry (ICP-MS). The total metal impurities were reduced to 0.8 ppm. The total organic impurities were reduced to 0.08% by gas chromatography-mass spectrometry (GC-MS), which met the requirements for subsequent high-selectivity reactions.

[0023] Step (2) Selective defluorination reaction The purified raw material was pumped into the reaction system at a feed rate of 0.3 mL / min, while high-purity nitrogen (purity ≥99.999%) was introduced. The nitrogen flow rate was controlled at 1.5 L / h to ensure that the liquid raw material and nitrogen were fully mixed before entering the reactor. Then, the mixture was introduced into a fixed-bed reactor (material: 316L stainless steel, inner diameter 20 mm, length 500 mm) filled with a special composite catalyst. The reactor was a three-stage gradient temperature control type, with a preheating stage temperature of 70℃, a reaction stage temperature of 100℃, and a stabilization stage temperature of 80℃. Each stage used an independent temperature control module (temperature control accuracy ±1℃). The reaction pressure was maintained at 0.2 MPa, and the reaction time was 2 hours.

[0024] Catalyst preparation: Al₂O₃ and ZrO₂ were mixed at a molar ratio of 4:1, and an appropriate amount of deionized water was added and stirred to form a uniform slurry. The slurry was aged at 50℃ for 18 hours, followed by calcination at 550℃ for 4 hours to obtain an Al₂O₃-ZrO₂ composite oxide support. After cooling to room temperature, the support was immersed in a 10% (w / w) triethanolamine aqueous solution at a liquid-to-solid ratio of 8:1 (mL / g). It was then immersed in an ultrasonic cleaner (300W) for 3 hours, followed by centrifugation and drying at 110℃ for 5 hours to obtain a specialized composite catalyst. Triethanolamine is loaded onto the support by forming hydrogen bonds and weak coordination with the hydroxyl groups on the surface of the Al₂O₃-ZrO₂ support. The hydroxyl and tertiary amine groups in the triethanolamine synergistically regulate the density and strength of Lewis acid / Brønsted base sites on the catalyst surface, thereby preferentially activating the fluorine atom at the β-position of the CF bond with the hydroxyl group, promoting its removal as HF, while simultaneously inhibiting α-fluorine removal and intramolecular dehydration side reactions. The specific surface area of ​​this catalyst is 200 m². 2 / g, with an average pore size of 3.5nm.

[0025] Catalyst loading: The catalyst in the reaction section is layered, with catalyst particles of 1.0 mm, 0.8 mm, and 0.5 mm in diameter sequentially packed along the material flow direction, at a packing density of 1.0 g / cm³. 3 After filling, the pressure drop of the bed was measured to be 0.03 MPa.

[0026] Step (3) Product Refining After the reaction product was condensed and collected, it was first subjected to vacuum distillation: the distillation temperature was 80℃, the system vacuum degree was 80Pa, and the reflux ratio was 1:3. After collecting the main fraction, it was washed twice with deionized water at 25℃, with the mass ratio of water to product being 1:1.5 each time. After washing, the organic phase was dried under vacuum: the temperature was 50℃, the vacuum degree was 40Pa, and the drying time was 3 hours, resulting in a colorless and transparent liquid product, which was denoted as sample E1.

[0027] Step (4) Compliance Testing The following tests were performed on E1: Purity and organic impurities: High performance liquid chromatography (HPLC, Shimadzu LC-20A) was used for analysis. The chromatographic column was a C18 column (4.6 mm × 250 mm, 5 μm), the column temperature was 30 ℃, the mobile phase was methanol-water (30:70, v / v), the flow rate was 1.0 mL / min, the detection wavelength was 210 nm, the injection volume was 10 μL, and the external standard method was used for quantification.

[0028] Fluoride ion residues: Analyzed by ion chromatography (IC, Thermo Fisher ICS-1100) with an anion exchange column (4.0 mm × 250 mm), column temperature 30 ℃, mobile phase 2.2 mmol / L NaHCO3-1.8 mmol / L Na2CO3 buffer, flow rate 1.0 mL / min, and detection by conductivity detector.

[0029] Test results: 2-Fluoroacrylate purity: 99.82%; The highest content of a single impurity: 0.03%; Fluoride ion residue: 0.4 ppm.

[0030] All results met the product quality control requirements (purity ≥ 99.8%, single impurity ≤ 0.05%, fluoride ion residue ≤ 0.5 ppm).

[0031] Step (5) Catalyst regeneration and recycling After the reaction, the reactor was switched to regeneration mode, using an ozone-nitrogen mixture prepared on-site by an ozone generator, with the ozone volume fraction controlled at 8% (monitored and adjusted in real time by an online UV ozone concentration meter). The deactivated catalyst was regenerated in situ at 180°C for 3 hours. During regeneration, an ozone concentration high-limit alarm (>12%) and an automatic nitrogen purging interlock were implemented to ensure operational safety. The regeneration gas space velocity was 300 h⁻¹. -1 After regeneration, the product is purged with high-purity nitrogen and cooled to 100°C before being directly added to the next batch of reaction. After 10 cycles, the yield and purity of the 10th batch of product (denoted as E1-10) are determined.

[0032] Example 2: Effect of different raw material ester groups Except for replacing the raw material with industrial-grade ethyl 1,1-difluoro-2-hydroxypropionate (R=C2H5), the other steps are the same as in Example 1. The initial typical impurity content of the raw material is at the same level as that of the methyl ester raw material used in Example 1. After being treated with the same purification steps, it meets the reaction requirements, and the resulting product is recorded as sample E2.

[0033] Example 3: Effect of different reaction temperatures The temperature of the reaction section was adjusted to 90°C, and the remaining steps were the same as in Example 1. The resulting product was denoted as sample E3.

[0034] Example 4: Effect of different catalyst ratios When preparing the special composite catalyst, the molar ratio of Al2O3 to ZrO2 was adjusted to 3:1, the mass fraction of triethanolamine was adjusted to 5%, and the remaining steps were the same as in Example 1. The resulting product was denoted as sample E4.

[0035] Example 5: The effect of different regeneration conditions In the catalyst regeneration step, the regeneration temperature was adjusted to 160°C, the volume fraction of ozone in the ozone-nitrogen mixture was adjusted to 6%, and the regeneration time was extended to 4 hours. The remaining steps were the same as in Example 1. Under these regeneration conditions, the catalyst was recycled 10 times, and the 10th batch of product was collected and recorded as sample E5-10.

[0036] Comparison Example 1: Catalyst-free modification Triethanolamine modification was not performed during catalyst preparation. Only the Al2O3-ZrO2 composite oxide support prepared according to the method in Example 1 was used as the catalyst. The remaining reaction and purification steps were the same as in Example 1. The resulting product was denoted as sample C1.

[0037] Comparison with Example 2: Non-gradient temperature controlled reactor A conventional isothermal fixed-bed reactor was used instead of the three-stage gradient temperature-controlled reactor. The overall temperature of the reactor was set and maintained at 100°C, with no preheating or stabilization stage. The remaining steps were the same as in Example 1, and the resulting product was designated as sample C2.

[0038] Comparison with Example 3: No raw material pretreatment Unpurified industrial-grade methyl 1,1-difluoro-2-hydroxypropionate (approximately 5 ppm of initial metal impurities and approximately 0.5% of organic impurities) was used directly as the reaction raw material, skipping the customized purification steps. The remaining reaction, purification, and detection steps were the same as in Example 1, and the resulting product was designated as sample C3.

[0039] Comparison with Example 4: Non-medical grade testing Only routine gas chromatography purity analysis was performed on the product prepared according to the method of Example 1 (the detection method was not optimized and confirmed for specific impurities and fluoride ion residues), and the complete and compliant testing procedure described in claim 8 and Example 1 was not performed. This sample did not obtain comprehensive pharmaceutical-grade quality evaluation data and is designated as sample C4.

[0040] Experimental Data Recording Table Experimental Data Analysis Explanation 1. The core role of catalysts in the modification of organic amines Comparing the data of Example 1 and Control Example 1, it is clear that modifying the Al2O3-ZrO2 support with triethanolamine is the key to obtaining highly selective hydrogen fluoride defluorination performance. Although the unmodified catalyst (C1) can initiate the reaction, its selectivity is poor, resulting in a significant decrease in product purity (98.50% vs 99.82%), a substantial increase in fluoride ion residue (2.5 ppm vs 0.4 ppm), and a severe loss in yield. This indicates that the organic amine modification effectively modulates the acid-base properties and active site distribution on the catalyst surface, preferentially promotes the selective removal of target fluoride atoms, and inhibits side reactions that lead to increased fluoride ion release.

[0041] 2. Process advantages of multi-stage gradient temperature controlled reactor Example 1 employed a gradient temperature control mode of preheating-reaction-stabilization, while Control Example 2 used a simple isothermal operation. The results showed that gradient temperature control not only improved the product purity (99.82% vs 99.40%) and yield (92.5% vs 85.6%), but more importantly, it controlled the residual fluoride ions at an extremely low level (0.4ppm vs 1.2ppm). This demonstrates that gradient temperature control is beneficial for the gradual activation of raw materials, the effective distribution of reaction heat, and the timely removal of products, reducing side reactions such as decomposition and polymerization caused by local overheating. These side reactions are often important sources of impurities such as fluoride ions. For heat-sensitive pharmaceutical intermediates such as 2-fluoroacrylic acid, this design is crucial for ensuring the quality of the final product.

[0042] 3. The fundamental contribution of raw material pretreatment to pharmaceutical-grade quality Example 1 involved targeted deep purification of industrial-grade raw materials, while Control Example 3 omitted this step. Although both underwent the same catalytic reaction and purification, the untreated raw materials directly resulted in significantly higher levels of residual fluoride ions (1.8 ppm) and organic impurities (0.15%) in the product compared to the pretreated case, and also reduced the yield. This verifies that trace amounts of metallic impurities (such as Fe, Cu, etc.) and specific organic impurities in the raw materials may play the role of non-selective catalysts or participate in side reactions during the reaction process, directly affecting the reaction selectivity and impurity profile. Therefore, starting with raw materials that meet pharmaceutical standards is the cornerstone for the stable production of pharmaceutical-grade products by the entire process.

[0043] 4. Economic efficiency and sustainability of catalyst regeneration process Data from Examples 1, E1-10, and E5-10 collectively demonstrate the effectiveness of the catalyst regeneration strategy of this invention. Under standard regeneration conditions, after 10 cycles, the catalyst activity remains good, and the product purity and key impurity indicators still fully comply with pharmacopoeia standards, with minimal yield decline. Optimizing regeneration conditions (E5-10) can further maintain performance. In-situ regeneration using an ozone-nitrogen mixture can effectively oxidize and remove surface carbon and strongly adsorbed fluorine-containing species from the catalyst, restoring its active sites. This regeneration method is mild and efficient, avoiding the high costs and waste disposal problems caused by frequent catalyst replacement, and providing strong support for achieving continuous, stable, and economical pharmaceutical-grade large-scale production.

[0044] 5. Overall adaptability of the process to biomedical applications The products of all embodiments (E1-E5-10) consistently meet the stringent requirements of the Pharmacopoeia of the People's Republic of China in terms of purity, content of individual impurities, and residual fluoride ions. This is not the result of optimization of a single technical point, but rather the result of the synergistic effect of the entire chain constructed by this invention, which includes "raw material standard control, highly selective catalytic reaction, multi-dimensional purification and refinement, and precise compliance testing." This system ensures that the produced 2-fluoroacrylic acid is not an ordinary chemical, but has a clear "pharmaceutical grade" identity, and can be directly and safely used for the subsequent synthesis of high-value-added drug intermediates or as a qualified raw material for vaccine adjuvants. This reflects the deep alignment of this invention with the needs of the biopharmaceutical industry from process to product.

[0045] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A process for preparing 2-fluoroacrylic acid based on selective defluorination of hydrogen, characterized in that, Using 1,1-difluoro-2-hydroxypropionate as shown in formula (I) as a raw material, 2-fluoroacrylic acid is prepared by selective dehydrofluorination reaction under the action of a special composite catalyst. The process includes the following steps: Formula (I): CHF2CH(OH)COOR, where R is a C1-C4 alkyl group; (1) Raw material pretreatment: The 1,1-difluoro-2-hydroxypropionate raw material is purified to control the content of metal impurities in the raw material to ≤1ppm and the content of organic impurities to ≤0.1%, so that the raw material meets the requirements of subsequent high-selectivity reaction; (2) Selective defluorination reaction: Pretreated 1,1-difluoro-2-hydroxypropionate is pumped into the reaction system at a feed rate of 0.1–0.5 mL / min, while an inert diluent is introduced simultaneously. The volumetric flow rate of the inert diluent is controlled at 0.5–2 L / h to ensure thorough mixing of the liquid feedstock and the inert diluent before entering the reactor. Subsequently, the mixture is introduced into a fixed-bed reactor packed with a special composite catalyst. The selective defluorination reaction is carried out at a reaction temperature of 80–120 °C and a reaction pressure of 0.1–0.3 MPa for 1–3 h. The special composite catalyst is composed of a metal oxide support and an organic amine modified component in a mass ratio of 8:2–9:1, wherein the metal oxide support is an Al2O3-ZrO2 composite oxide, and the organic amine modified component is triethanolamine; and the specific surface area of ​​the special composite catalyst is 150–250 m². 2 / g, with a pore size of 2-5nm; (3) Product purification: After the reaction product is condensed and collected, it is subjected to vacuum distillation, water washing to remove impurities and vacuum drying in sequence to obtain high-purity 2-fluoroacrylic acid; (4) Product quality control: The refined 2-fluoroacrylic acid is tested to ensure that the product purity is ≥99.8%, the content of a single impurity is ≤0.05%, and the residual amount of fluoride ions is ≤0.5ppm.

2. The preparation process according to claim 1, characterized in that, In step (1), the raw material purification is carried out by molecular distillation at a distillation temperature of 60-80℃ and a vacuum degree of ≤50Pa.

3. The preparation process according to claim 1, characterized in that, In step (2), the inert diluent is one or a mixture of nitrogen and argon.

4. The preparation process according to claim 1, characterized in that, The preparation method of the special composite catalyst in step (2) is as follows: Al2O3 and ZrO2 are mixed in a molar ratio of 3:1 to 5:1, deionized water is added and stirred into a slurry, aged at 40 to 60°C for 12 to 24 hours, and then calcined at 500 to 600°C for 3 to 5 hours to obtain Al2O3-ZrO2 composite oxide; after cooling the composite oxide to room temperature, it is immersed in a 5% to 15% triethanolamine aqueous solution and ultrasonically impregnated for 2 to 4 hours, wherein the liquid-to-solid ratio of the ultrasonic impregnation is 5:1 to 10:1 (mL / mL). g); then centrifuged and dried at 100-120℃ for 4-6 h to obtain a special composite catalyst; the triethanolamine is loaded on the support by forming hydrogen bonds and weak coordination with the hydroxyl groups on the surface of Al2O3-ZrO2 support. The hydroxyl and tertiary amine groups in its molecule synergistically regulate the density and intensity of Lewis acid / Brønsted base sites on the catalyst surface, thereby preferentially activating the fluorine atom in the CF bond that is at the β position with the hydroxyl group, promoting its removal in the form of HF, while inhibiting α-fluorine removal and intramolecular dehydration side reactions.

5. The preparation process according to claim 1, characterized in that, The conditions for vacuum distillation in step (3) are: distillation temperature 70-90℃, vacuum degree ≤100Pa, and reflux ratio 1:2-1:

5.

6. The preparation process according to claim 1, characterized in that, In step (3), deionized water is used for washing to remove impurities. The washing temperature is 20-30℃, and the number of washings is 2-3 times. The mass ratio of water to reaction product is 1:1-1:2 for each washing.

7. The preparation process according to claim 1, characterized in that, The conditions for vacuum drying in step (3) are: drying temperature 40-60℃, vacuum degree ≤50Pa, and drying time 2-4h.

8. The preparation process according to claim 1, characterized in that, In step (4), impurity detection employs a combination of high-performance liquid chromatography (HPLC) and ion chromatography. The HPLC detection conditions are as follows: a C18 column with dimensions of 4.6 mm × 250 mm and a particle size of 5 μm; a column temperature of 30 °C; a mobile phase of methanol-water with a volume ratio of 30:70; a flow rate of 0.8–1.2 mL / min; a detection wavelength of 210 nm; and an injection volume of 10 μL. Ion chromatography is used to detect residual fluoride ions. The detection conditions are as follows: an anion exchange column with dimensions of 4.0 mm × 250 mm; a column temperature of 30 °C; a mobile phase of 2.2 mmol / L sodium bicarbonate-1.8 mmol / L sodium carbonate buffer solution; a flow rate of 1.0 mL / min; and a conductivity detector. Quantitative analysis is performed using the external standard method during the detection process.

9. The preparation process according to claim 1, characterized in that, In step (2), the fixed-bed reactor is a multi-stage gradient temperature-controlled reactor. The reactor is divided into a preheating section, a reaction section, and a stabilization section along the material flow direction. The temperature of the preheating section is 60-80℃, the temperature of the reaction section is 80-120℃, and the temperature of the stabilization section is 70-90℃. The temperature of each section is independently controlled, and the temperature difference control accuracy is ±2℃. The special composite catalyst loaded in the reaction section adopts a layered loading method. The particle size of the catalyst decreases from 1.0mm to 0.5mm along the material flow direction, and the loading density is 0.8-1.2g / cm³. 3 The bed pressure drop is ≤0.05MPa.

10. The preparation process according to claim 1, characterized in that, The preparation process also includes step (5) catalyst regeneration and recycling: After the reaction is completed, an ozone-nitrogen mixture prepared on-site by an ozone generator is used, wherein the volume fraction of ozone in the mixture is controlled at 5-10%, and the deactivated catalyst is regenerated in situ at 150-200℃ for 2-4 hours; during the regeneration process, an ozone concentration high limit alarm (>12%) and an automatic nitrogen purging interlock device are set to ensure safe operation; after the regenerated catalyst is purged with nitrogen and cooled to the reaction temperature, it is directly put into the next batch of reaction, and the number of cycles is ≥10 times. After a single cycle, the yield of 2-fluoroacrylic acid decreases by ≤1.5%, and the purity of the product still meets the product quality control requirements of step (4).

Images