Fluorine-containing medical intermediate ethyl difluoroacetate and preparation method thereof

Abstract

The invention discloses a fluorine-containing medical intermediate ethyl difluoroacetate and a preparation method thereof, and belongs to the technical field of synthesis of organic fluorine compounds. The method comprises the following steps: firstly, taking tetrafluoroethylene and ethanol as raw materials, and reacting under the action of a basic catalyst to prepare an intermediate 1, 1, 2, 2-tetrafluoroethyl ether with stable properties; and then gasifying the intermediate, and performing catalytic cracking through a modified gamma-aluminum oxide catalyst bed layer subjected to specific high-temperature pre-fluorination treatment under the mild condition of 160-190 DEG C to generate high-activity difluoroacetyl fluoride in situ, and finally, directly introducing the cracking gas containing difluoroacetyl fluoride into a low-temperature reaction solution containing ethanol and an acid-binding agent without separation, and carrying out esterification reaction. According to the method, a brand-new synthesis route and a special catalyst are adopted, reaction conditions are mild, the cracking step selectivity is high, the production efficiency and the total yield are remarkably improved through integrated process design, and the technological process is simple, safe and reliable.

Description

Technical Field

[0001] This invention relates to the field of organofluorine compound synthesis technology, and in particular to a fluorine-containing pharmaceutical intermediate, ethyl difluoroacetate, and its preparation method. Background Technology

[0002] Ethyl difluoroacetate is an important fluorine-containing fine chemical. Due to its unique chemical structure and properties, it is widely used as a key intermediate in the synthesis of novel pesticides, pharmaceuticals, and functional materials. With the rapid development of the field of fluorine-containing drugs and materials, the market demand for high-quality ethyl difluoroacetate is increasing. Therefore, developing stable, efficient, economical, and environmentally friendly preparation methods is of great practical significance.

[0003] Currently, the traditional industrial process for preparing ethyl difluoroacetate typically relies on the direct esterification reaction of difluoroacetic acid and ethanol. However, this method faces inherent challenges in practical applications. On the one hand, difluoroacetic acid, as the starting material, is difficult to prepare, expensive, and highly corrosive, which not only increases production costs but also places higher demands on production equipment and operational safety. On the other hand, direct esterification is a typical reversible equilibrium reaction. To obtain a high yield, excess reactants or complex dehydration processes are often required to drive the reaction to equilibrium. This complicates post-treatment processes and may generate large amounts of acidic wastewater, putting pressure on environmental protection.

[0004] To circumvent these problems, the industry has explored other synthetic routes, such as preparation through multi-step transformations of other fluorinated compounds. However, these alternative routes are often difficult to scale up for industrial production due to lengthy steps, low overall yields, or the need for harsh reaction conditions and expensive special reagents. Particularly when it comes to the cracking steps of fluorinated ethers, extremely high reaction temperatures are typically required to break the chemical bonds, but at high temperatures, side reactions increase dramatically, product selectivity is difficult to control, and catalysts are prone to carbon buildup and deactivation, leading to unstable production processes and making continuous operation difficult.

[0005] Therefore, there is an urgent need in this field for a novel technical solution that can efficiently and stably prepare ethyl difluoroacetate by starting from inexpensive and readily available raw materials and through a route with mild process conditions, high reaction selectivity, simple process, and suitability for industrial production. Summary of the Invention

[0006] The technical problem to be solved by this invention is to provide a fluorinated pharmaceutical intermediate, ethyl difluoroacetate, and its preparation method. Existing technologies for the cracking of fluorinated ether compounds often face problems such as harsh reaction conditions, low product selectivity, numerous side reactions, and easy catalyst deactivation.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution.

[0008] The first aspect of this invention provides a fluorinated pharmaceutical intermediate, ethyl difluoroacetate.

[0009] The catalyst is a fluorinated alumina catalyst. This catalyst is prepared by pre-fluorinating a γ-alumina substrate with a fluorine-containing gas at a temperature of 200-400°C for 1-5 hours.

[0010] The inventors discovered that pre-fluorination of conventional γ-alumina under specific conditions can alter its surface chemical properties. Within a specific temperature range of 200-400℃, fluorine-containing gases react with the alumina surface to form Al-F bonds and construct Lewis and Brønsted acid active sites with specific acid strengths and types. These reconstructed active sites possess unique adsorption and activation capabilities for the CO and CF bonds of fluorinated ether compounds. This specific activation can directionally promote the cleavage of 1,1,2,2-tetrafluoroethyl ether molecules along the pathway leading to the formation of difluoroacetyl fluoride and ethylene, while effectively inhibiting side reactions such as deep cracking and HF elimination, thus achieving highly selective catalytic cracking under relatively mild conditions. Furthermore, the stable surface structure formed after fluorination also improves the chemical stability and lifespan of the catalyst in fluorine-containing reaction systems.

[0011] As a preferred technical solution, the fluorine-containing gas is hydrogen fluoride, sulfur tetrafluoride, or a mixture of fluorine and nitrogen with a volume fraction of 2% to 10%.

[0012] A second aspect of the present invention provides a method for preparing ethyl difluoroacetate.

[0013] The method includes the following steps: (1) 1,1,2,2-tetrafluoroethyl ether was prepared by reacting tetrafluoroethylene with ethanol under the action of an alkaline catalyst. (2) Under the action of a catalyst, the 1,1,2,2-tetrafluoroethyl ether obtained in step (1) is subjected to catalytic cracking at a temperature of 160-190°C to obtain a gas containing difluoroacetyl fluoride; wherein the catalyst is the fluorinated alumina catalyst described in the first aspect of the present invention. (3) The gas containing difluoroacetyl fluoride obtained in step (2) is passed into the reaction solution containing ethanol to carry out the esterification reaction to obtain ethyl difluoroacetate.

[0014] This method proposes a novel three-step synthetic route. First, gaseous, difficult-to-control tetrafluoroethylene is converted into a liquid, stable 1,1,2,2-tetrafluoroethyl ether intermediate through a well-established addition reaction. This intermediate is easy to purify, store, and quantitatively deliver.

[0015] Subsequently, in the core catalytic cracking step, the aforementioned fluorinated alumina catalyst is used to induce site-specific cracking of 1,1,2,2-tetrafluoroethyl ether under mild conditions of 160-190°C, efficiently generating highly reactive difluoroacetyl fluoride gas. This step avoids directly processing the highly corrosive and difficult-to-prepare difluoroacetic acid, instead generating its equivalent, more reactive acyl fluoride, in situ through a controlled cracking reaction.

[0016] Finally, the highly reactive difluoroacetyl fluoride gas generated from the pyrolysis was directly captured and esterified. Since acyl fluorides are far more reactive than carboxylic acids, this esterification reaction can be carried out rapidly and completely at low temperatures, with high product yields and simple purification.

[0017] In a preferred embodiment, the residence time for the catalytic cracking in step (2) is 30–40 seconds. This residence time is matched with the catalyst activity and reaction temperature, ensuring a balance between the full conversion of ETPE and the selectivity of the target product.

[0018] In a preferred embodiment, the reaction in step (1) is carried out at a temperature of 50-85°C and a pressure of 0.8-1.2 MPa. The alkaline catalyst is potassium hydroxide, and its amount is 0.5-2.0 mol% of the molar amount of ethanol used in step (1). These are the process conditions for achieving efficient conversion in step (1).

[0019] In a preferred embodiment, the ethanol-containing reaction solution in step (3) further contains triethylamine, and the esterification reaction is carried out at a temperature of 0-10°C. Triethylamine, as an acid-binding agent, can immediately neutralize the byproduct hydrogen fluoride generated in the esterification reaction, thereby protecting the product ester from acid decomposition and promoting the forward shift of the reaction equilibrium. Low temperature conditions are beneficial for controlling the strongly exothermic esterification reaction and reducing the formation of byproducts.

[0020] In a more preferred embodiment, the molar amount of ethanol in step (3) is 1.2-2.0 times the total molar amount of 1,1,2,2-tetrafluoroethyl ether prepared in step (1), and the molar amount of triethylamine is 1.0-1.2 times the total molar amount of 1,1,2,2-tetrafluoroethyl ether. This ensures sufficient reactants so that the highly reactive difluoroacetyl fluoride can be completely converted.

[0021] In a complete embodiment, the method further includes the step of preparing the fluorinated alumina catalyst: pre-fluorinating the γ-alumina substrate at 200-400°C with a fluorine-containing gas selected from hydrogen fluoride, sulfur tetrafluoride, or a mixture of fluorine and nitrogen with a volume fraction of 2% to 10% for 1 to 5 hours.

[0022] In summary, the present invention has at least one of the following beneficial technical effects: 1. High selectivity in catalytic cracking and good product purity: This invention prepares a unique fluorinated alumina catalyst by subjecting a γ-alumina substrate to a specific high-temperature prefluorination treatment. The specific active sites formed on the catalyst surface can precisely identify and activate the target chemical bonds of 1,1,2,2-tetrafluoroethyl ether molecules, directionally promoting their conversion to difluoroacetyl fluoride. This significantly suppresses side reactions such as deep cracking and elimination during the catalytic cracking step, ensuring high selectivity for key intermediates and laying the foundation for obtaining high-purity ethyl difluoroacetate.

[0023] 2. The reaction conditions are mild, making the production process safer and more economical: Thanks to the introduction of the aforementioned highly efficient and specialized catalysts, the core catalytic cracking step can be carried out efficiently within a milder temperature range than traditional cracking processes. This not only significantly reduces energy consumption during production, meeting the requirements of green chemical development, but more importantly, it greatly improves operational safety, avoiding the stringent equipment requirements and potential risks caused by high temperature and high pressure, making the entire preparation method more suitable for large-scale, continuous industrial production.

[0024] 3. The raw material route is novel, and the process flow is reasonable and controllable: This invention innovatively designs a three-step synthesis route of "stabilization-controlled pyrolysis-efficient conversion". This method first converts the difficult-to-store and controllable gaseous raw material tetrafluoroethylene into a stable liquid intermediate, facilitating precise metering and transportation. Subsequently, highly reactive acyl fluoride is generated in situ through controlled catalytic pyrolysis, avoiding the direct handling of highly corrosive and difficult-to-prepare acidic raw materials. The entire process route is logically clear and the material flow is smooth, making the control of the production process simpler and more reliable.

[0025] 4. Integrated reaction design significantly improves production efficiency: This method ingeniously integrates the pyrolysis and esterification steps seamlessly, achieving "in-situ generation-online reaction" of the key intermediate difluoroacetyl fluoride. The highly reactive gas generated by pyrolysis is directly introduced into the esterification reactor for conversion without separation and purification, greatly simplifying the process flow and eliminating the need for collection, storage, and transfer of unstable intermediates. This not only avoids material loss but also significantly shortens the production cycle and greatly improves overall production efficiency.

[0026] 5. High final product yield and good atom economy: By employing highly reactive difluoroacetyl fluoride as the esterification precursor and supplementing it with an acid-binding agent, the final esterification reaction can proceed rapidly and completely at low temperatures. The acid-binding agent effectively neutralizes reaction byproducts, protects the target product from decomposition, and simultaneously promotes the forward shift of the reaction equilibrium. The combination of a highly selective pyrolysis step and a high-conversion esterification step ensures a high overall yield from initial feedstock to final product, demonstrating excellent atom economy. Detailed Implementation

[0027] This invention provides a fluorinated pharmaceutical intermediate, ethyl difluoroacetate, and its preparation method. Example 1

[0028] 1. Preparation of Fluorinated Alumina Catalysts 100g of γ-alumina substrate with a particle size of 40 mesh was dried at 130℃ for 6 hours. It was then packed into a tube furnace and heated to 300℃ under nitrogen protection. Once the temperature was reached, a mixture of 6% fluorine and nitrogen gas was introduced into the furnace at a flow rate controlled at 120 mL / min for a pre-fluorination treatment lasting 3 hours. After the treatment, the substrate was cooled to room temperature under nitrogen protection to obtain the fluorinated alumina catalyst.

[0029] 2. Preparation of intermediate 1,1,2,2-tetrafluoroethyl ether (ETPE) In a 5L high-pressure reactor, 25.4g of potassium hydroxide (equivalent to 1.2mol% of the ethanol used) was added, and 2200 mL of anhydrous ethanol was introduced. After purging with nitrogen, tetrafluoroethylene was introduced into the reactor until the initial pressure reached 1.1 MPa. Stirring was started, and the temperature inside the reactor was raised to and maintained at 70°C. When the pressure dropped to 1.0 MPa, tetrafluoroethylene was added to maintain the pressure. The reaction was stopped after 5 hours. After washing with water, separation, and distillation, the fraction collected at 101.5°C yielded 1,1,2,2-tetrafluoroethyl ether (ETPE).

[0030] 3. Preparation of Ethyl difluoroacetate The fluorinated alumina catalyst obtained in step 1 of Example 1 was packed into a tubular pyrolyzer, and the catalyst bed temperature was heated to 175°C. The ETPE obtained in step 2 was pumped into a preheater at 95°C at a flow rate of 25.00 kg / h for gasification, and then passed into the pyrolyzer with a residence time of 35 seconds to obtain pyrolyzed gas containing difluoroacetyl fluoride.

[0031] Simultaneously, in a three-necked flask equipped with a stirrer, 2400 mL of anhydrous ethanol (1.6 times the total molar amount of ETPE) and 1700 mL of triethylamine (1.1 times the total molar amount of ETPE) were added, and the mixture was cooled to 5°C using an ice-water bath. The aforementioned cracked gas was directly passed into this mixture to carry out the esterification reaction. After the reaction was completed, the reaction solution was subjected to atmospheric distillation, and the fraction collected at 105.5°C yielded ethyl difluoroacetate. Example 2

[0032] 1. Preparation of Fluorinated Alumina Catalysts 100g of γ-alumina substrate with a particle size of 60 mesh was dried at 110℃ for 8 hours. It was then packed into a tube furnace and heated to 200℃ under nitrogen protection. Once the temperature was reached, hydrogen fluoride gas was introduced into the furnace at a flow rate of 50mL / min for a pre-fluorination treatment of 1 hour. After the treatment, the substrate was cooled to room temperature under nitrogen protection to obtain the fluorinated alumina catalyst.

[0033] 2. Preparation of intermediate 1,1,2,2-tetrafluoroethyl ether (ETPE) In a 5L high-pressure reactor, 9.8g of potassium hydroxide (equivalent to 0.5mol% of the ethanol used) was added, and 2000mL of anhydrous ethanol was introduced. After purging with nitrogen, tetrafluoroethylene was introduced into the reactor until the initial pressure reached 1.0 MPa. Stirring was started, and the temperature inside the reactor was raised to and maintained at 50°C. When the pressure dropped to 0.8 MPa, tetrafluoroethylene was added to maintain the pressure. The reaction was stopped after 4 hours. The reaction solution was washed with water, separated, and distilled. The fraction collected at 100°C yielded 1,1,2,2-tetrafluoroethyl ether (ETPE).

[0034] 3. Preparation of Ethyl difluoroacetate The fluorinated alumina catalyst obtained in step 1 of Example 2 was packed into a tubular pyrolyzer, and the catalyst bed temperature was heated to 160°C. The ETPE obtained in step 2 was pumped into a preheater at 90°C at a flow rate of 20.00 kg / h for gasification, and then passed into the pyrolyzer with a residence time of 30 seconds to obtain pyrolyzed gas containing difluoroacetyl fluoride.

[0035] Simultaneously, in a three-necked flask equipped with a stirrer, 2000 mL of anhydrous ethanol (1.2 times the total molar amount of ETPE) and 1400 mL of triethylamine (1.0 times the total molar amount of ETPE) were added, and the mixture was cooled to 0°C using an ice-water bath. The aforementioned cracked gas was directly passed into this mixture to carry out the esterification reaction. After the reaction was completed, the reaction solution was subjected to atmospheric distillation, and the fraction collected at 104°C yielded ethyl difluoroacetate. Example 3

[0036] 1. Preparation of Fluorinated Alumina Catalysts 100g of γ-alumina substrate with a particle size of 20 mesh was dried at 150℃ for 4 hours. It was then packed into a tube furnace and heated to 400℃ under nitrogen protection. Once the temperature was reached, sulfur tetrafluoride gas was introduced into the furnace at a flow rate controlled at 200 mL / min for a pre-fluorination treatment lasting 5 hours. After the treatment, the substrate was cooled to room temperature under nitrogen protection to obtain the fluorinated alumina catalyst.

[0037] 2. Preparation of intermediate 1,1,2,2-tetrafluoroethyl ether (ETPE) In a 5L high-pressure reactor, 55.5g of potassium hydroxide (equivalent to 2.0 mol% of the ethanol used) was added, and 2500 mL of anhydrous ethanol was introduced. After purging with nitrogen, tetrafluoroethylene was introduced into the reactor until the initial pressure reached 1.2 MPa. Stirring was started, and the temperature inside the reactor was raised to and maintained at 85°C. When the pressure dropped to 0.9 MPa, tetrafluoroethylene was added to maintain the pressure. The reaction was stopped after 6 hours. After washing with water, separation, and distillation, the fraction collected at 103°C yielded 1,1,2,2-tetrafluoroethyl ether (ETPE).

[0038] 3. Preparation of Ethyl difluoroacetate The fluorinated alumina catalyst obtained in step 1 of Example 3 was packed into a tubular pyrolyzer, and the catalyst bed temperature was heated to 190°C. The ETPE obtained in step 2 was pumped into a preheater at 100°C at a flow rate of 30.00 kg / h for gasification, and then passed into the pyrolyzer with a residence time of 40 seconds to obtain pyrolyzed gas containing difluoroacetyl fluoride.

[0039] Simultaneously, in a three-necked flask equipped with a stirrer, 3000 mL of anhydrous ethanol (2.0 times the total molar amount of ETPE) and 2200 mL of triethylamine (1.2 times the total molar amount of ETPE) were added, and the mixture was cooled to 10°C using an ice-water bath. The aforementioned cracked gas was directly passed into this mixture to carry out the esterification reaction. After the reaction was completed, the reaction solution was subjected to atmospheric distillation, and the fraction collected at 107°C yielded ethyl difluoroacetate. Comparative Example 1: Compared with Example 1, the difference is that in step 1, the preparation of fluorinated alumina catalyst is not carried out, and in step 3, γ-alumina that has not undergone any pre-fluorination treatment and has only been dried at 130°C for 6 hours is directly used as the catalyst for catalytic cracking. All other aspects are the same.

[0040] Comparative Example 2: Compared with Example 1, the difference is that in step 1, the temperature of the pre-fluorination treatment is set to 150°C, which is lower than the 200-400°C range required by this invention. All other aspects are the same.

[0041] Comparative Example 3: Compared with Example 1, the difference is that in step 3, the temperature of the catalyst bed is set to 130°C, which is lower than the 160-190°C range required by the present invention, while the rest are the same.

[0042] Comparative Example 4: Compared with Example 1, the difference is that in step 3, when the esterification reaction is carried out, only 2400 mL of anhydrous ethanol is added to the three-necked flask, and triethylamine is not added. All other aspects are the same.

[0043] Test Example 1: Comparative Test of Catalyst Prefluorination Treatment Effect Experimental steps: Catalyst loading and reaction preparation: Two identical catalytic cracking-esterification reaction apparatuses were used. In the tubular cracker of the first apparatus, the fluorinated alumina catalyst prepared according to step 1 of Example 1 was loaded. In the split-tube cracker of the second apparatus, the γ-alumina catalyst, as described in Comparative Example 1, without pre-fluorination treatment, was loaded. The catalyst bed temperature of both apparatuses was raised to and maintained at 175°C.

[0044] Catalytic cracking and gas sampling: The 1,1,2,2-tetrafluoroethyl ether (ETPE) prepared according to step 2 of Example 1 was pumped into the preheaters of two separate units at a flow rate of 25.00 kg / h for catalytic cracking. After the reaction stabilized, gaseous products from the cracking were collected periodically at the cracker outlet using a gas bag for subsequent analysis.

[0045] Data analysis and recording: The collected gas samples were immediately analyzed using gas chromatography (GC). The ETPE conversion rate was calculated by comparing the peak area changes of ETPE before and after the reaction. The relative content of the target product, difluoroacetyl fluoride, in all gaseous products was calculated (as an indicator of selectivity) by analyzing the product components.

[0046] Yield calculation: Both sets of equipment were run until the esterification reaction was completed. The crude difluoroethyl product was purified by distillation, and the mass of the purified product was accurately weighed. The yield of the final product, ethyl difluoroethyl, was calculated based on the amount of ETPE input.

[0047] Experimental data: Table 1 Performance comparison test data between Example 1 and Comparative Example 1 Experiment Summary: Comparative test results clearly show that using a catalyst that has undergone specific pre-fluorination treatment for catalytic cracking results in significantly better ETPE conversion, selectivity for the target intermediate difluoroacetyl fluoride, and yield of the final product ethyl difluoroacetate than the scheme that directly uses an untreated γ-alumina catalyst.

[0048] This significant difference stems from a fundamental alteration of the catalyst surface. High-temperature pre-fluorination treatment at 200-400℃ forms specific Al-F bonds and reconstructed acidic active sites on the γ-alumina surface. These unique active sites effectively adsorb and activate 1,1,2,2-tetrafluoroethyl ether molecules, and directionally promote their controlled catalytic cracking along the pathway to difluoroacetyl fluoride and ethylene, thereby achieving the high conversion and high selectivity shown in the data.

[0049] In contrast, conventional γ-alumina without pre-fluorination treatment, as shown in Comparative Example 1, lacks this specifically designed active center. Its surface exhibits low activity under reaction conditions and cannot efficiently select the reaction pathway, resulting in a large amount of ETPE remaining unconverted. The converted portion undergoes deep cracking or generates other byproducts, leading to an extremely low relative content of the target intermediate, difluoroacetyl fluoride, ultimately resulting in a poor overall yield of ethyl difluoroacetate. Therefore, specific pre-fluorination treatment of the catalyst is a key technological foundation for achieving the efficient and highly selective preparation method proposed in this invention. Test Example 2: Comparative Test of the Effect of Catalyst Preparation Temperature Experimental steps: Catalyst preparation and loading: Two identical catalytic cracking-esterification reaction apparatuses were used. In the tubular cracker of the first apparatus, a fluorinated alumina catalyst prepared according to step 1 of Example 1 (pre-fluorination temperature 300°C) was loaded. In the split-tube cracker of the second apparatus, a catalyst pre-fluorinated at 150°C as described in Comparative Example 2 was loaded. The catalyst bed temperature of both apparatuses was raised to and maintained at 175°C.

[0050] Catalytic cracking and data acquisition: The 1,1,2,2-tetrafluoroethyl ether (ETPE) prepared according to step 2 of Example 1 was pumped into the preheaters of two separate units at a flow rate of 25.00 kg / h for catalytic cracking. After the reaction stabilized, gaseous products after cracking were collected periodically at the cracker outlet using a gas bag.

[0051] Data analysis and recording: Gas chromatography (GC) was used to analyze the collected gas samples. The ETPE conversion rate was calculated by comparing the peak area changes of ETPE before and after the reaction. The relative content of the target product, difluoroacetyl fluoride, in all gaseous products was calculated by analyzing the product components.

[0052] Yield calculation: Both sets of equipment were run until the esterification reaction was completed. The crude difluoroethyl product was purified by distillation, and the mass of the purified product was accurately weighed. The yield of the final product, ethyl difluoroethyl, was calculated based on the amount of ETPE input.

[0053] Experimental data: Table 2 Comparative test data on the effect of catalyst preparation temperature Experiment Summary: Experimental results show that the pre-fluorination temperature of the catalyst is a key factor determining its catalytic performance. The catalyst prepared at 300℃ exhibits extremely high ETPE conversion and excellent selectivity for the target product difluoroacetyl fluoride in the subsequent catalytic cracking reaction, resulting in a high final product yield. In contrast, the catalyst prepared at the lower temperature of 150℃ shows significantly inferior performance across all indicators.

[0054] The underlying mechanism of this phenomenon lies in the fact that the temperature range of 200-400°C provides the necessary activation energy for an effective chemical reaction between fluorine-containing gases and the surface of γ-alumina. Within this temperature window, as shown in Example 1, the alumina surface can be sufficiently fluorinated, reconstructing Lewis acid and Brønsted acid active sites with specific acid strengths and spatial configurations. These specially formed active centers are key to the efficient adsorption and activation of ETPE molecules and guiding their directional cleavage to generate difluoroacetyl fluoride.

[0055] In Comparative Example 2, the pre-fluorination temperature of 150°C is far below the energy threshold required to form highly efficient active sites. At this low temperature, the fluorination reaction is insufficient and incomplete, failing to construct a sufficient number and type of active centers on the alumina surface. The surface state shows only limited improvement compared to untreated alumina, thus hindering effective catalysis and selective control of the reaction pathway. This directly leads to insufficient ETPE conversion and increased side reactions, ultimately severely impacting the overall yield of ethyl difluoroethylene. This fully demonstrates the necessity of the 200-400°C pre-fluorination temperature range for achieving the technical effects of this invention. Test Example 3: Comparative Test of the Effect of Catalytic Cracking Temperature Experimental steps: Preparation of the reaction apparatus: Two identical catalytic cracking-esterification reaction apparatuses were used. The same batch of fluorinated alumina catalyst, prepared according to step 1 of Example 1, was packed into the tubular crackers of both apparatuses. The catalyst bed temperature of the first apparatus was raised to and maintained at 175°C (Example 1 conditions). The catalyst bed temperature of the second apparatus was raised to and maintained at 130°C (Comparative Example 3 conditions).

[0056] Catalytic cracking and gas sampling: The 1,1,2,2-tetrafluoroethyl ether (ETPE) prepared according to step 2 of Example 1 was pumped into the preheaters of two separate units at a flow rate of 25.00 kg / h for catalytic cracking. After the reaction stabilized, gaseous products after cracking were collected periodically at the cracker outlet using a gas bag.

[0057] Data analysis and recording: Gas chromatography (GC) was used to analyze the collected gas samples. The ETPE conversion rate was calculated by comparing the peak area changes of ETPE before and after the reaction. The relative content of the target product, difluoroacetyl fluoride, in all gaseous products was calculated by analyzing the product components.

[0058] Yield calculation: Both sets of equipment were run until the esterification reaction was completed. The crude difluoroethyl product was purified by distillation, and the mass of the purified product was accurately weighed. The yield of the final product, ethyl difluoroethyl, was calculated based on the amount of ETPE input.

[0059] Experimental data: Table 3 Comparative test data on the effect of catalytic cracking temperature Experiment Summary: The results of this comparative test clearly demonstrate the decisive role of catalytic cracking temperature in the success or failure of the reaction. At the optimal temperature of 175°C, the conversion of ETPE, the selectivity to the target intermediate difluoroacetyl fluoride, and the yield of the final product were all at extremely high levels. However, when the reaction temperature was reduced to 130°C, even using the exact same optimized catalyst, all performance indicators deteriorated sharply.

[0060] The fundamental reason for this phenomenon lies in chemical reaction kinetics. While the fluorinated alumina catalyst designed in this invention can effectively adsorb ETPE molecules at its surface active sites, sufficient energy is still required to overcome the corresponding activation energy barrier before site-directed cleavage of the CO bonds can occur. The temperature range of 160-190℃ provides just the right amount of thermal energy, enabling the ETPE molecules adsorbed at the active sites to efficiently convert into difluoroacetyl fluoride and ethylene. Simultaneously, this energy level is insufficient to trigger large-scale deep cracking or other side reactions, thus achieving a balance between high conversion rate and high selectivity.

[0061] Conversely, at a low temperature of 130℃, as shown in Comparative Example 3, the thermal energy provided by the system is insufficient to effectively drive the target pyrolysis reaction. Even when most ETPE molecules are adsorbed by the catalyst, they cannot obtain enough energy to overcome the activation barrier, resulting in an extremely slow reaction rate and low ETPE conversion. Furthermore, the lower temperature may complicate the reaction pathway, with some molecules potentially redirecting to other side reaction pathways with lower energy barriers, leading to a significant decrease in the selectivity of the target product. Ultimately, this renders the overall yield of ethyl difluoroethylene far from practically useful. This demonstrates that a pyrolysis temperature of 160-190℃ is a crucial process condition necessary for synergistic effects with the catalyst of this invention to achieve efficient preparation.

[0062] Test Example 4: Comparative Test of the Role of Acid-Binding Agents in the Esterification Step Experimental steps: Preparation of esterification reaction solution: Take two identical receiving reaction apparatuses (three-necked flasks). In the first flask, add 2400 mL of anhydrous ethanol and 1700 mL of triethylamine as described in Example 1. In the second flask, add only 2400 mL of anhydrous ethanol as described in Comparative Example 4. Place both flasks in an ice-water bath to maintain the liquid temperature at 5°C.

[0063] Integrated reaction: Prepare a catalytic cracking apparatus operating under the conditions of Example 1. Divide its outlet gas stream into two equal streams via a three-way valve, and introduce them into the two prepared three-necked flasks at the same flow rate to carry out the esterification reaction.

[0064] Product analysis and recording: After the gas flow was completed, samples were immediately taken from both three-necked flasks. Gas chromatography (GC) was used to analyze the two crude products, and the purity of ethyl difluoroacetate in the crude products was calculated and recorded using the peak area normalization method.

[0065] Yield calculation: The reaction solutions in both flasks were purified by the same atmospheric distillation process. The mass of the fraction collected at 104–107 °C was accurately weighed, and the yield of the final product, ethyl difluoroacetate, was calculated based on the theoretical amount of feed entering each flask.

[0066] Experimental data: Table 4 Comparative test data on the effects of acid-binding agents (triethylamine) The results of this comparative test clearly demonstrate the necessity of introducing triethylamine as an acid-binding agent in the esterification step. In the system containing triethylamine, the purity of the crude product and the yield of the final purified product remained at very high levels. However, after removing triethylamine, even under identical conditions, the purity and yield of the product decreased catastrophically.

[0067] The chemical mechanism behind this result lies in the effective management of the esterification reaction byproducts. When difluoroacetyl fluoride reacts with ethanol to produce the target product, ethyl difluoroacetate, a highly corrosive byproduct—hydrogen fluoride (HF)—is inevitably generated. In the system of Example 1, triethylamine, as an alkaline substance, can immediately and in situ neutralize the newly generated hydrogen fluoride, converting it into a stable quaternary ammonium salt. This process not only eliminates the corrosion and decomposition damage to equipment and products caused by strong acids, but more importantly, it removes a reaction product, greatly promoting the forward esterification reaction according to the principle of chemical equilibrium, ensuring the completeness of the reaction.

[0068] In contrast, in the triethylamine-free system of Comparative Example 4, the generated hydrogen fluoride continuously accumulated in the low-temperature ethanol solution. The high concentration of strongly acidic HF catalyzes the reverse hydrolysis (or alcoholysis) of the already generated target product, ethyl difluoroacetate, leading to product loss. Furthermore, it may catalyze a series of complex side reactions, such as ethanol dehydration, resulting in a sharp decrease in the purity of the crude product. Ultimately, a large amount of the target product is destroyed in the acidic environment, and the complex composition significantly increases the difficulty and loss of subsequent distillation purification, collectively contributing to the low final yield. Therefore, integrating the pyrolysis step with the esterification step containing an acid-binding agent is the key synergistic design of this invention for achieving efficient and high-purity preparation of the target product.

[0069] 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 fluorinated pharmaceutical intermediate, ethyl difluoroacetate, characterized in that, The catalyst is a fluorinated alumina catalyst, which is prepared by pre-fluorinating a γ-alumina substrate with a fluorine-containing gas at a temperature of 200-400℃ for 1-5 hours.

2. The catalyst according to claim 1, characterized in that, The fluorine-containing gas is hydrogen fluoride, sulfur tetrafluoride, or a mixture of fluorine and nitrogen with a volume fraction of 2% to 10%.

3. A method for preparing ethyl difluoroacetate, characterized in that, Includes the following steps: (1) 1,1,2,2-tetrafluoroethyl ether was prepared by reacting tetrafluoroethylene with ethanol under the action of an alkaline catalyst. (2) Under the action of a catalyst, the 1,1,2,2-tetrafluoroethyl ether obtained in step (1) is subjected to catalytic cracking at a temperature of 160-190°C to obtain a gas containing difluoroacetyl fluoride; wherein the catalyst is the fluorinated alumina catalyst as described in claim 1 or 2. (3) The gas containing difluoroacetyl fluoride obtained in step (2) is passed into the reaction solution containing ethanol to carry out the esterification reaction to obtain ethyl difluoroacetate.

4. The method according to claim 3, characterized in that, The residence time for catalytic cracking in step (2) is 30 to 40 seconds.

5. The method according to claim 3, characterized in that, The reaction in step (1) is carried out at a temperature of 50-85℃ and a pressure of 0.8-1.2MPa.

6. The method according to claim 3 or 5, characterized in that, The alkaline catalyst mentioned in step (1) is potassium hydroxide.

7. The method according to claim 6, characterized in that, The amount of potassium hydroxide used is 0.5-2.0 mol of the amount of ethanol used in step (1).

8. The method according to claim 3, characterized in that, The ethanol-containing reaction solution described in step (3) also contains triethylamine, and the esterification reaction is carried out at a temperature of 0-10°C.

9. The method according to claim 8, characterized in that, The molar amount of ethanol is 1.2-2.0 times the total molar amount of 1,1,2,2-tetrafluoroethyl ether prepared in step (1), and the molar amount of triethylamine is 1.0-1.2 times the total molar amount of 1,1,2,2-tetrafluoroethyl ether.

10. The method according to claim 3, characterized in that, The method further includes the step of preparing the fluorinated alumina catalyst: pre-fluorinating the γ-alumina substrate at 200-400°C with a fluorine-containing gas selected from hydrogen fluoride, sulfur tetrafluoride, or a mixture of fluorine and nitrogen with a volume fraction of 2% to 10% for 1 to 5 hours.