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CN-122010711-A - Synthesis method of 2,4, 5-trifluoro phenylacetic acid

CN122010711ACN 122010711 ACN122010711 ACN 122010711ACN-122010711-A

Abstract

The application discloses a synthesis method of 2,4, 5-trifluoro-phenylacetic acid, which belongs to the technical field of organic chemical industry, and comprises the steps of taking 1,2, 4-trifluoro-benzene as a raw material, reacting with tetrachloromethane and aluminum chloride passivated by pseudo-boehmite to generate 2,4, 5-trifluoro- (trichloromethyl) benzene, separating and extracting an oil phase after the reaction is finished, dripping zinc chloride aqueous solution into the oil phase, hydrolyzing the 2,4, 5-trifluoro- (trichloromethyl) benzene to generate 2,4, 5-trifluoro-benzoyl chloride, adding azidomethane and silver oxide, and converting acyl chloride into carboxylic acid by utilizing the Arndt-Eistert reaction to generate 2,4, 5-trifluoro-phenylacetic acid.

Inventors

  • LI FANG
  • GUO XUANYU
  • WANG ZHAOPING

Assignees

  • 山东国邦药业有限公司
  • 国邦医药集团股份有限公司

Dates

Publication Date
20260512
Application Date
20260410

Claims (10)

  1. 1. The synthesis method of the 2,4, 5-trifluoro-phenylacetic acid is characterized by comprising the following steps of: firstly, adding 1,2, 4-trifluoro benzene, tetrachloromethane and pseudo-boehmite to passivate aluminum chloride in a reaction container, heating for reaction, and performing post-treatment to obtain crude 2,4, 5-trifluoro- (trichloromethyl) benzene; secondly, adding the crude 2,4, 5-trifluoro- (trichloromethyl) benzene into a reaction container, heating, dropwise adding zinc chloride aqueous solution, carrying out heat preservation reaction after the dropwise adding is finished, and carrying out post-treatment after the reaction is finished to obtain 2,4, 5-trifluoro benzoyl chloride; And thirdly, adding the 2,4, 5-trifluoro benzoyl chloride into a reaction container, cooling, adding diazomethane dissolved in tetrahydrofuran, reacting with silver oxide, and after the reaction is finished, carrying out post-treatment to obtain the 2,4, 5-trifluoro phenylacetic acid.
  2. 2. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein the molar ratio of 1,2, 4-trifluorobenzene to tetrachloromethane in step (one) is 1:3.0-5.0,1,2,4-trifluorobenzene to pseudo-boehmite passivated aluminum chloride is 1:0.4.
  3. 3. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein said elevated temperature in step (one) is 50-70 ℃ and the reaction time is 5h.
  4. 4. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein the molar ratio of 1,2, 4-trifluorobenzene to zinc chloride in the aqueous solution of zinc chloride in step (II) is 1:0.1-0.3.
  5. 5. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein said aqueous solution of zinc chloride has a concentration of 40 wt%.
  6. 6. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (two), the temperature is raised to 50-70 ℃, the time for dropwise adding zinc chloride aqueous solution is 60 min, and the time for thermal insulation reaction is 60 min.
  7. 7. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein the molar ratio of 1,2, 4-trifluorobenzene to tetrahydrofuran in step (III) is 1:0.30-0.36.
  8. 8. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (III), the molar ratio of 1,2, 4-trifluorobenzene to diazomethane is 1:1.0-1.2, and the molar ratio of 1,2, 4-trifluorobenzene to silver oxide is 1:0.1.
  9. 9. The method for synthesizing 2,4, 5-trifluoro phenylacetic acid according to claim 1, wherein the temperature of the temperature reduction in the step (three) is-10 ℃.
  10. 10. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein said reaction time in step (III) is 1-5 h.

Description

Synthesis method of 2,4, 5-trifluoro phenylacetic acid Technical Field The application belongs to the technical field of organic chemical industry, and particularly relates to a synthesis method of 2,4, 5-trifluoro-phenylacetic acid. Background 2,4, 5-Trifluoro-phenylacetic acid is an important medical intermediate, is mainly used for synthesizing and preparing oral hypoglycemic agents sitagliptin and regagliptin, and is also a novel fluorine-containing herbicide raw material. Sitagliptin is developed and sold by Merck corporation in the United states, belongs to dipeptidyl peptidase-4 (DPP-4) inhibitor, can be singly or combined into compound medicine for treating type 2 diabetes, and has the advantages of high safety and less side effect. The common synthetic route for domestic synthesis of 2,4, 5-trifluoro-phenylacetic acid is to take 1,2, 4-trifluoro-benzene as raw material, obtain 2,4, 5-trifluoro-benzyl chloride through chloromethylation reaction of paraformaldehyde and chlorinating agent, obtain 2,4, 5-trifluoro-phenylacetonitrile through cyanation reaction of cyanation reagent, obtain 2,4, 5-trifluoro-phenylacetic acid crude product through hydrolysis in solvent, and obtain 2,4, 5-trifluoro-phenylacetic acid pure product through recrystallization. The chloromethylation, cyanation and other reactions are used in the whole route process, the chloromethylation raw materials and the cyanation raw materials used in the reaction are extremely toxic and highly carcinogenic, the requirement on equipment corrosiveness is high, the yield of the electrophilic reaction by chloromethylation and the reaction of 1,2, 4-trifluorobenzene is difficult to improve, a large amount of highly toxic and carcinogenic waste liquid can be generated after the reaction is finished, and the requirements of efficient and green environment-friendly production are not met. Patent CN102690166a reports a method for preparing 2,4, 5-trifluorophenylacetic acid from 1,2, 4-trifluorobenzene, which comprises adding sulfuric acid into 1,2, 4-trifluorobenzene and paraformaldehyde, introducing hydrogen chloride gas, performing chloromethylation reaction on sulfuric acid solution with concentration of 80-90% as chlorinating agent to obtain 2,4, 5-trifluorobenzyl chloride, performing cyanidation reaction in cyanidation reaction reagent to obtain 2,4, 5-trifluorobenzyl cyanide, heating and hydrolyzing in acidic or alkaline aqueous solution, and post-treating to obtain 2,4, 5-trifluorophenylacetic acid. Patent CN1749232a reports a method for preparing 2,4, 5-trifluorophenylacetic acid from 1,2, 4-trifluorobenzene, which comprises reacting 1,2, 4-trifluorobenzene with paraformaldehyde under the reaction condition of chlorinating agent to obtain 2,4, 5-trifluorobenzyl chloride, then carrying out cyanidation reaction in solvent to obtain 2,4, 5-trifluorobenzyl cyanide, carrying out reflux hydrolysis under acidic or alkaline condition to obtain crude 2,4, 5-trifluorophenylacetic acid, and then obtaining high-purity 2,4, 5-trifluorophenylacetic acid by recrystallization. Patent CN109400459B reports a method for preparing 2,4, 5-trifluorophenylacetic acid from 2, 4-dichlorobenzene as raw material, mixing 2, 4-dichlorobenzene with nitric acid and sulfuric acid for reaction, nitrifying to obtain 2, 4-dichloro-5-fluoronitrobenzene, then reacting with fluorinating agent to obtain 2,4, 5-trifluoronitrobenzene, introducing chlorine to chloro the obtained 2,4, 5-trifluoronitrobenzene to obtain 2,4, 5-trifluorochlorobenzene, coupling with ethyl cyanoacetate for reaction to 2-cyano-2- (2, 4, 5) -trifluorophenylacetic acid ethyl ester, finally stirring and hydrolyzing in excessive sodium hydroxide solution, and acidifying to obtain 2,4, 5-trifluorophenylacetic acid. Patent CN101659611a reports a method for preparing 2,4, 5-trifluorophenylacetic acid from 1,2, 4-trifluorobenzene, adding chlorinating agent into 1,2, 4-trifluorobenzene and paraformaldehyde to carry out chloromethylation reaction, hydrolyzing the reaction product in ice water to obtain 2,4, 5-trifluorobenzyl chloride, reacting 2,4, 5-trifluorobenzyl chloride with cyanidation agent in ion solution to obtain 2,4, 5-trifluorobenzyl cyanide, hydrolyzing under acidic or alkaline condition, purifying to obtain 2,4, 5-trifluorophenylacetic acid. Patent CN100516014C reports a method for preparing 2,4, 5-trifluorophenylacetic acid from 1,2, 4-trifluorobenzene, adding a chlorinating agent into 1,2, 4-trifluorobenzene and paraformaldehyde to perform chloromethylation reaction to obtain 2,4, 5-trifluorobenzyl chloride, and performing carbonylation reaction between 2,4, 5-trifluorobenzyl chloride and carbon monoxide under the action of a catalyst tetracarbonylcobalt salt to obtain 2,4, 5-trifluorophenylacetic acid. The process has the main defects that 1, the reaction raw materials are high in toxicity, carcinogenicity and high in requirement on equipment corrosiveness after chloromethylation and cyanation reac