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CN-121990910-A - Fluorine-containing pharmaceutical intermediate ethyl difluoroacetate and preparation method thereof

CN121990910ACN 121990910 ACN121990910 ACN 121990910ACN-121990910-A

Abstract

The invention discloses a fluorine-containing pharmaceutical intermediate ethyl difluoroacetate and a preparation method thereof, belonging to the technical field of organic fluorine compound synthesis. The method comprises the steps of firstly reacting tetrafluoroethylene and ethanol serving as raw materials under the action of an alkaline catalyst to prepare an intermediate 1, 2-tetrafluoroethyl ether with stable properties, gasifying the intermediate, then carrying out catalytic pyrolysis on the intermediate under the mild condition of 160-190 ℃ through a modified gamma-alumina catalyst bed subjected to specific high-temperature pre-fluorination treatment to generate high-activity difluoro acetyl fluoride in situ, and finally directly introducing pyrolysis gas containing difluoro acetyl fluoride into a low-temperature reaction liquid containing ethanol and an acid binding agent for esterification reaction without separation. The invention adopts a brand new synthetic route and a special catalyst, realizes the modernization of reaction conditions, has high selectivity of cracking steps, and remarkably improves the production efficiency and the total yield through integrated process design, and has simple process flow, safety and reliability.

Inventors

  • XU SONG
  • LV YUNPING
  • GUO FENG
  • WANG JIANGUO
  • MA ZHENXIANG
  • FENG QIXING
  • Leng Xuanjin
  • TAN RONG
  • MA XIANGHONG

Assignees

  • 贵州华尔盛新材料有限公司

Dates

Publication Date
20260508
Application Date
20251205

Claims (10)

  1. 1. The fluorine-containing pharmaceutical intermediate ethyl difluoroacetate is characterized in that the catalyst is a fluoridized alumina catalyst, and is prepared by pre-fluoridized treatment of gamma-alumina base material for 1-5 hours at the temperature of 200-400 ℃.
  2. 2. The catalyst according to claim 1, wherein the fluorine-containing gas is hydrogen fluoride, sulfur tetrafluoride, or a mixture of 2% -10% by volume of fluorine gas and nitrogen gas.
  3. 3. The preparation method of ethyl difluoroacetate is characterized by comprising the following steps: (1) Tetrafluoroethylene and ethanol react under the action of an alkaline catalyst to prepare 1, 2-tetrafluoroethyl ether; (2) Under the action of a catalyst, carrying out catalytic cracking on the 1, 2-tetrafluoroethyl ether prepared in the step (1) at 160-190 ℃ to obtain a gas containing difluoro acetyl fluoride, wherein the catalyst is the fluoridized alumina catalyst in the claim 1 or 2; (3) And (3) introducing the difluoro acetyl fluoride-containing gas obtained in the step (2) into the ethanol-containing reaction liquid to perform esterification reaction to obtain difluoro ethyl acetate.
  4. 4. The method of claim 3, wherein the residence time of the catalytic cracking in step (2) is 30 to 40 seconds.
  5. 5. A process according to claim 3, wherein the reaction in step (1) is carried out at a temperature of 50-85 ℃ and a pressure of 0.8-1.2 MPa.
  6. 6. The method according to claim 3 or 5, wherein the basic catalyst in step (1) is potassium hydroxide.
  7. 7. The method of claim 6, wherein the potassium hydroxide is used in an amount of 0.5 to 2.0 mol% of the molar amount of ethanol used in step (1).
  8. 8. A process according to claim 3, wherein the ethanol-containing reaction solution in step (3) further comprises triethylamine, and the esterification reaction is carried out at a temperature of 0 to 10 ℃.
  9. 9. The process of claim 8, wherein the molar amount of ethanol is 1.2 to 2.0 times the total molar amount of 1, 2-tetrafluoroethyl ether produced in step (1), and the molar amount of triethylamine is 1.0 to 1.2 times the total molar amount of 1, 2-tetrafluoroethyl ether.
  10. 10. The method according to claim 3, further comprising the step of preparing the fluorided alumina catalyst, wherein the gamma-alumina substrate is subjected to a pre-fluoriding treatment with a fluorine-containing gas selected from the group consisting of hydrogen fluoride, sulfur tetrafluoride, and a mixture of 2% -10% by volume of fluorine gas and nitrogen gas at 200-400 ℃ for 1-5 hours.

Description

Fluorine-containing pharmaceutical intermediate ethyl difluoroacetate and preparation method thereof Technical Field The invention relates to the technical field of synthesis of organic fluorine compounds, in particular to a fluorine-containing medical intermediate ethyl difluoroacetate and a preparation method thereof. Background Ethyl difluoroacetate is an important fine fluorine-containing chemical, and is widely used as a key intermediate for synthesizing novel pesticides, medicines and functional materials due to its unique chemical structure and properties. With the rapid development of the fields of fluorine-containing medicines and materials, the market has increasingly increased demands for high-quality ethyl difluoroacetate, so that the development of a stable, efficient, economical and environment-friendly preparation method has important practical significance. Currently, the traditional process route for the industrial preparation of ethyl difluoroacetate generally relies on the direct esterification of difluoroacetic acid with ethanol. However, this approach presents inherent challenges in practical applications. On the one hand, difluoroacetic acid as starting material is inherently difficult to prepare, expensive and highly corrosive, which not only increases the production cost, but also places higher demands on the safety of production equipment and operation. On the other hand, direct esterification is a typical reversible equilibrium reaction, and to obtain a higher yield, it is often necessary to use excessive reactants or complex dehydration processes to promote the reaction equilibrium, which complicates the post-treatment process and may generate a large amount of acidic wastewater, putting pressure on environmental protection. To circumvent the above problems, other synthetic routes have also been explored, for example, by multi-step transformations of other fluorochemicals. However, these alternative routes are often difficult to implement on a large scale due to lengthy steps, low overall yields, or the need to use harsh reaction conditions and expensive special reagents. Particularly, when the cracking step of the fluorine-containing ether compound is involved, extremely high reaction temperature is usually required to break chemical bonds, but side reactions are greatly increased at high temperature, the selectivity of the product is difficult to control, and meanwhile, the catalyst is extremely easy to be deactivated by carbon deposition, so that the production process is unstable and continuous operation is difficult. Therefore, a brand new technical scheme is urgently needed in the field, and the scheme can be used for efficiently and stably preparing ethyl difluoroacetate from cheap and easily available raw materials through a route which is mild in process conditions, high in reaction selectivity, concise in flow and suitable for industrial production. Disclosure of Invention The invention aims to provide a fluorine-containing medical intermediate ethyl difluoroacetate and a preparation method thereof. In the prior art, when cracking fluorine-containing ether compounds, the problems of harsh reaction conditions, low product selectivity, multiple side reactions, easy deactivation of catalysts and the like are often faced. In order to solve the technical problems, the invention provides the following technical scheme. The first aspect of the invention provides a fluorine-containing pharmaceutical intermediate ethyl difluoroacetate. The catalyst is a fluorided alumina catalyst. The catalyst is prepared by pre-fluorinating a gamma-alumina substrate for 1-5 hours at the temperature of 200-400 ℃ by using fluorine-containing gas. The inventors have found that the surface chemistry of conventional gamma-alumina can be altered by pre-fluorination treatment under specific conditions. In a specific temperature range of 200-400 ℃, fluorine-containing gas reacts with the surface of aluminum oxide to form Al-F bonds and construct Lewis acid and Bronsted acid active sites with specific acid strength and acid type. These reconstituted active sites have unique adsorption and activation capacities for the C-O and C-F bonds of fluoroethers. The specific activation can directionally promote the 1, 2-tetrafluoroethyl ether molecules to break along the path for generating difluoroacetyl fluoride and ethylene, and simultaneously effectively inhibit side reactions such as deep cracking, HF elimination and the like, thereby realizing high-selectivity catalytic cracking under relatively mild conditions. In addition, the stable surface structure formed after the fluorination treatment also improves the chemical stability and the service life of the catalyst in a fluorine-containing reaction system. As a preferable technical scheme, the fluorine-containing gas is hydrogen fluoride, sulfur tetrafluoride or a mixed gas of 2% -10% of fluorine gas and nitrogen gas by volume fraction. The second aspect of