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CN-121988248-A - Method for continuously preparing 5- (trifluoromethyl) -1H-tetrazole sodium salt

CN121988248ACN 121988248 ACN121988248 ACN 121988248ACN-121988248-A

Abstract

The invention relates to the field of organic synthesis, in particular to a method for continuously preparing 5- (trifluoromethyl) -1H-tetrazole sodium salt. The method comprises the steps of mixing trifluoroacetamide and 3-methylpyridine to obtain a first mixture, mixing phosphorus oxychloride and 3-methylpyridine to obtain a second mixture, mixing the first mixture and the second mixture in a continuous feeding mode, maintaining steady-state reaction, continuously obtaining a reaction liquid, carrying out gas-liquid separation on the reaction liquid to obtain liquid and gas, quenching the liquid, washing the gas by 3-methylpyridine, then introducing the gas into a mixed solution of sodium azide and acetone for absorption, filtering to obtain a filter cake, and leaching to obtain 5- (trifluoromethyl) -1H-tetrazole sodium salt. The purity of the product prepared by the method is more than or equal to 99.3%, the yield is 84-91%, and the method is easy for industrial production.

Inventors

  • FU MIN
  • FU LEIHAN
  • KANG LITAO
  • SONG ZIJIE

Assignees

  • 上海熵延新能源科技有限公司

Dates

Publication Date
20260508
Application Date
20251212

Claims (10)

  1. 1. A system for continuously preparing 5- (trifluoromethyl) -1H-tetrazole sodium salt is characterized by comprising a feeding unit (1), a continuous reaction device (2) and a gas-liquid separation device (3) which are sequentially communicated, wherein a liquid outlet of the gas-liquid separation device (3) is communicated with a feeding port of a quenching kettle (4), a gas outlet of the gas-liquid separation device (3) is communicated with a gas inlet of a gas washing kettle (5), a gas outlet of the gas washing kettle (5) is communicated with a gas inlet of an absorption kettle (6), and the system is used for inputting trifluoroacetamide, phosphorus oxychloride and 3-methylpyridine into the continuous reaction device (2) from the feeding unit (1) for reaction, then carrying out gas-liquid separation through the gas-liquid separation device (3), washing gas through the gas washing kettle (5), and then absorbing and filtering the gas to obtain the 5- (trifluoromethyl) -1H-tetrazole sodium salt through the absorption kettle (6).
  2. 2. The system according to claim 1, wherein the feeding unit (1) comprises a first batching kettle (11) and a second batching kettle (12) which are respectively communicated with the feeding end of the continuous reaction device (2), the first batching kettle (11) and the second batching kettle (12) are arranged in parallel, the first batching kettle (11) is used for mixing trifluoroacetamide and 3-methylpyridine, the second batching kettle (12) is used for mixing phosphorus oxychloride and 3-methylpyridine, and/or the continuous reaction device (2) is selected from one or more of an overflow kettle, a tubular reactor, a dynamic tubular reactor or a microreactor, and/or the absorption kettle (6) is an absorption kettle with a filtering device, and/or sodium azide and acetone are placed in the absorption kettle (6), and/or an exhaust gas absorption kettle (7) is arranged at the exhaust end of the absorption kettle (6) in communication.
  3. 3. The system according to claim 2, wherein a first feeding pump (13) is arranged on a pipeline connected with the first continuous reaction device (11) and the second continuous reaction device (2), and/or a second feeding pump (14) is arranged on a pipeline connected with the second continuous reaction device (2), and/or a plurality of continuous reaction devices (2) are arranged in series through the pipeline, two adjacent continuous reaction devices (2) are communicated through the pipeline, the feeding end of the first continuous reaction device (2) is respectively communicated with the first continuous reaction device (11) and the second continuous reaction device (12), and the discharging end of the last continuous reaction device (2) is communicated with the feeding end of the gas-liquid separation device (3).
  4. 4. A method for continuously preparing 5- (trifluoromethyl) -1H-tetrazole sodium salt is characterized by comprising the following steps: (1) Mixing trifluoroacetamide and 3-methylpyridine to obtain a first mixture; (2) Mixing phosphorus oxychloride and 3-methylpyridine to obtain a mixture II; (3) Mixing the first mixture and the second mixture in a continuous feeding mode, and maintaining a steady-state reaction to continuously obtain a reaction solution; (4) And (3) carrying out gas-liquid separation on the reaction liquid to obtain liquid and gas, quenching the liquid, washing the gas through 3-methylpyridine, then introducing the gas into a mixed solution of sodium azide and acetone for absorption, filtering to obtain a filter cake, and leaching to obtain 5- (trifluoromethyl) -1H-tetrazole sodium salt.
  5. 5. The method according to claim 4, wherein the mass ratio of the trifluoroacetamide to the 3-methylpyridine in the step (1) is 1:2-10.
  6. 6. The method according to claim 4, wherein the mass ratio of phosphorus oxychloride to 3-methylpyridine in the step (2) is 1:1.5-10.
  7. 7. The method according to claim 4, wherein the molar ratio of the trifluoroacetamide in the first mixture to the phosphorus oxychloride in the second mixture in the step (3) is 1:0.5-2, and/or the reaction temperature in the step (3) is 80-143 ℃ and the reaction time is 30-100min.
  8. 8. The method according to claim 4, wherein the scrubbing temperature in the step (4) is 0-5 ℃, and/or the organic solvent is adopted for leaching in the step (4), and/or the mass-volume ratio of sodium azide and acetone in the step (4) is 60-65g:430-460ml, and/or the absorption temperature in the step (4) is 25-30 ℃.
  9. 9. A process for preparing 5- (trifluoromethyl) -1H-tetrazole sodium salt according to any one of claims 4-8.
  10. 10. The sodium salt of 5- (trifluoromethyl) -1H-tetrazole according to claim 9, wherein the purity of the sodium salt of 5- (trifluoromethyl) -1H-tetrazole is greater than or equal to 99.3% and the yield is 84-91%.

Description

Method for continuously preparing 5- (trifluoromethyl) -1H-tetrazole sodium salt Technical Field The invention relates to the field of organic synthesis, in particular to a method for continuously preparing 5- (trifluoromethyl) -1H-tetrazole sodium salt. Background The 5- (trifluoromethyl) -1H-tetrazole sodium salt is taken as an important organic synthetic building block and functional molecule, and the core structure of the building block is composed of two key pharmacophores of tetrazole ring and trifluoromethyl. Among them, tetrazole ring is a five-membered aromatic heterocycle composed of four nitrogen atoms and one carbon atom, and is regarded as a classical bioisostere of carboxylic acid group, which means that it is similar to carboxylate in steric arrangement and electronic properties, but generally imparts higher metabolic stability and lipid solubility to the parent molecule, thereby significantly affecting its biological activity. Meanwhile, trifluoromethyl is a strong electron withdrawing group, has high lipophilicity and excellent chemical and metabolic stability, and can be introduced into molecules to help regulate acidity and lipid water distribution coefficient of the molecules and optimize interaction with biological targets, so that bioavailability and selectivity of the drug are improved. As such, 5-trifluoromethyl-1H-tetrazole building blocks have received great attention in the development of medicines and pesticides. At present, the chemical synthesis of the compound mainly depends on two known routes, but has obvious defects which limit the industrial application of the compound. Route 1 (see U.S. Pat. No. 4,320,124,1 to International application W02002020495A3 and Chinese patent CN 1592743A) was prepared by reflux reaction of trifluoroacetamide as the starting material with tris (azido) chlorosilane in acetonitrile. The core problem of this route is that the reagent tris (azido) chlorosilane used is not only expensive per se, but also has a significant potential hazard due to its instability and high energy, which makes the route unsuitable for large-scale production from both safety and cost points of view. Scheme 2 (reported in Journal of Fluorine Chemistry, 2008, 129, 1199-1205) also starts with trifluoroacetamide, which is first dehydrated with trifluoroacetic anhydride in pyridine to form a gaseous trifluoroacetonitrile intermediate, which is then condensed to a liquid using liquid nitrogen, slowly warmed and passed into an acetonitrile solution of sodium azide for reaction. The bottleneck of this process is that the liquid nitrogen condensation and transfer operation of the highly toxic intermediate trifluoroacetonitrile is complex, accompanied by extremely high safety risks, and the energy consumption is enormous, which together limit its feasibility in industrial scenarios. In summary, the prior art syntheses all face the common challenges of either relying on high-risk, high-cost reagents or inevitably involving the formation and handling of high-risk intermediates in the process path, and generally employing batch-type operations with safety and control stubs. Therefore, a new synthetic route which can reduce the use of high-risk reagents, effectively control toxic intermediates and is suitable for continuous safe production is developed, and the urgent practical demand is brought to the promotion of the industrial application of the 5- (trifluoromethyl) -1H-tetrazole sodium salt. Disclosure of Invention In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide a method for continuously preparing 5- (trifluoromethyl) -1H-tetrazole sodium salt, which is used for solving the problems that the synthesis of 5- (trifluoromethyl) -1H-tetrazole sodium salt in the prior art either relies on high-risk and high-cost reagents or inevitably involves the generation and treatment of high-risk intermediates in a process path, and the batch operation of safety and control short plates is commonly adopted. To achieve the above and other related objects, the present invention is achieved by the following technical solutions. The first aspect of the invention provides a system for continuously preparing 5- (trifluoromethyl) -1H-tetrazole sodium salt, which comprises a feeding unit, a continuous reaction device and a gas-liquid separation device which are sequentially communicated, wherein a liquid outlet of the gas-liquid separation device is communicated with a feeding port of a quenching kettle, a gas outlet of the gas-liquid separation device is communicated with a gas inlet of a gas washing kettle, and the system is used for inputting trifluoroacetamide, phosphorus oxychloride and 3-methylpyridine into the continuous reaction device from the feeding unit for reaction, then carrying out gas-liquid separation through the gas-liquid separation device, washing gas through the gas washing kettle, and then absorbing and filtering by an absorption kettle