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CN-121990901-A - Preparation method of valproic acid

CN121990901ACN 121990901 ACN121990901 ACN 121990901ACN-121990901-A

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of valproic acid. The preparation method of valproic acid comprises the following steps of firstly mixing malonic acid diester, allyl halide, alkaline solution and first catalyst, and then performing allylation reaction to obtain diallyl malonic acid diester, wherein the structural formula of the malonic acid diester is Wherein R is C1-C4 straight chain alkyl or C3-C4 branched chain alkyl, carrying out hydrogenation reaction after second mixing of the diallyl malonate, hydrogen, an organic solvent and a second catalyst to obtain dipropyl malonate, and carrying out decarboxylation after hydrolyzing the dipropyl malonate to obtain valproic acid. The preparation method provided by the invention has the advantages that the safety of the preparation raw materials is high, the harm to human bodies and the environment is reduced, meanwhile, the preparation process is simple and easy to operate, the production safety is greatly improved, the production time is shortened, and the production efficiency is improved.

Inventors

  • PENG HUI
  • ZENG SHUN
  • LV HUICHAO
  • Peng Zegen
  • ZHU JUNLING
  • MO YANYANG

Assignees

  • 湖南省湘中制药有限公司

Dates

Publication Date
20260508
Application Date
20260126

Claims (10)

  1. 1. The preparation method of valproic acid is characterized by comprising the following steps: The method comprises the steps of carrying out first mixing on malonic acid diester, allyl halide, alkaline solution and first catalyst, and then carrying out allylation reaction to obtain diallyl malonic acid diester, wherein the structural formula of the malonic acid diester is Wherein R is C1-C4 straight-chain alkyl or C3-C4 branched-chain alkyl; the diallyl malonate diester, hydrogen, an organic solvent and a second catalyst are subjected to hydrogenation reaction after being mixed for the second time, so as to obtain the dipropyl malonate diester; and (3) hydrolyzing the dipropylmalonic acid diester, and then decarboxylating to obtain valproic acid.
  2. 2. The preparation method of the allyl halide according to claim 1, wherein the allyl halide comprises allyl chloride, allyl bromide or allyl iodide, and the molar ratio of the malonic diester to the allyl halide is 1:2-20.
  3. 3. The method according to claim 1, wherein the alkaline compound in the alkaline solution comprises sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or potassium carbonate; the solvent in the alkaline solution comprises water, methanol or ethanol; the molar ratio of the malonic diester to the alkaline compound in the alkaline solution is 1:1-4.
  4. 4. The method of preparing according to claim 1, wherein the first catalyst comprises one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, polyethylene glycol, and triethylamine; The molar ratio of the malonic diester to the first catalyst is 1:0-0.5.
  5. 5. The method according to any one of claims 1 to 4, wherein the allylation reaction is performed in a dynamic tubular reactor; the temperature of the allylation reaction is 20-140 ℃, the pressure is 0-10 MPa, and the time is 1-60 min.
  6. 6. The method according to claim 1, wherein the organic solvent comprises methanol, ethanol, acetic acid, tetrahydrofuran, or ethyl acetate; The second catalyst comprises a palladium on carbon catalyst, palladium-silica, palladium-alumina, platinum on carbon catalyst, raney nickel, nickel-silica, or nickel on carbon catalyst.
  7. 7. The method of claim 1, wherein the molar ratio of diallyl malonate to hydrogen is 1:2-6.
  8. 8. The process according to claim 1, 6 or 7, wherein the hydrogenation reaction is carried out in a fixed bed; The temperature of the hydrogenation reaction is 20-180 ℃, the pressure is 0-10 MPa, the mass airspeed is 0.1-10 h -1 , and the residence time is 1-60 min.
  9. 9. The preparation method according to claim 1, wherein the hydrolysis step comprises the steps of carrying out a reflux reaction after third mixing of the hydrogenated system and an alkali solution, concentrating the reflux reaction system, carrying out fourth mixing with water, adjusting the pH value to be less than or equal to 1.5, filtering, and washing the obtained solid with water to obtain dipropylmalonic acid.
  10. 10. The method according to claim 1, wherein the decarboxylation is performed at a temperature of 160-180 ℃ for a time of 1-3 hours.

Description

Preparation method of valproic acid Technical Field The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of valproic acid. Background The valproic acid chemical name is 2-propyl valeric acid, the CAS registration number is 99-66-1, is an important medical intermediate, can be used for preparing anti-epileptic drugs sodium valproate and magnesium valproate, and has wide application prospects in the medical industry. Valproic acid is widely studied as a precursor for preparing antiepileptic drugs. For example, in patent US4127604, cyanoacetate and bromopropane are used as starting materials, sodium alkoxide is used as an alkali reagent for catalytic reaction to prepare 2-cyano-2-propyl methyl valerate, the 2-cyano-2-propyl methyl valerate is hydrolyzed, acidified and subjected to high Wen Tuosuan to obtain valproic acid, the valproic acid is converted into valproic amide through hydrolysis of 80% sulfuric acid, nitrous acid is further added into a reaction system for oxidation to obtain valproic acid, and in the reaction process, sodium nitrite and acid such as sulfuric acid react to generate nitrous acid and then are further decomposed into nitric oxide and nitrogen dioxide, wherein the nitric oxide and the nitrogen dioxide are acidic toxic oxides, so that metal equipment is corroded, the environment is polluted greatly, and the operation is also dangerous to a certain extent. In patent CN111349003A, ethyl valerate is used as a starting material, a catalytic reaction is carried out in an ether solution by using a pyrrole metal catalyst to generate 2-propyl-ethyl valerate, then the 2-propyl-ethyl valerate is hydrolyzed into a sodium valproate crude product by using sodium hydroxide, ethanol is distilled off, and acidification and desalination are carried out to obtain the valproic acid, but the method uses ether as a solvent, industrialization has certain danger, and simultaneously uses pyrrole metal as a catalyst, so that the pyrrole metal is not common in industry and has certain danger. In summary, a safe production method of valproic acid is needed. Disclosure of Invention In view of the above, the invention provides a preparation method of valproic acid, which has the advantages of high safety of raw materials, simple and easy operation of the preparation process and great improvement of production safety. In order to solve the technical problems, the invention provides a preparation method of valproic acid, which comprises the following steps: The method comprises the steps of carrying out first mixing on malonic acid diester, allyl halide, alkaline solution and first catalyst, and then carrying out allylation reaction to obtain diallyl malonic acid diester, wherein the structural formula of the malonic acid diester is Wherein R is C1-C4 straight-chain alkyl or C3-C4 branched-chain alkyl; the diallyl malonate diester, hydrogen, an organic solvent and a second catalyst are subjected to hydrogenation reaction after being mixed for the second time, so as to obtain the dipropyl malonate diester; and (3) hydrolyzing the dipropylmalonic acid diester, and then decarboxylating to obtain valproic acid. Preferably, the allyl halide comprises allyl chloride, allyl bromide or allyl iodide, and the molar ratio of the malonic diester to the allyl halide is 1:2-20. Preferably, the alkaline compound in the alkaline solution comprises sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or potassium carbonate; the solvent in the alkaline solution comprises water, methanol or ethanol; the molar ratio of the malonic diester to the alkaline compound in the alkaline solution is 1:1-4. Preferably, the first catalyst comprises one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, polyethylene glycol, and triethylamine; The molar ratio of the malonic diester to the first catalyst is 1:0-0.5. Preferably, the allylation reaction is carried out in a dynamic tubular reactor; the temperature of the allylation reaction is 20-140 ℃, the pressure is 0-10 MPa, and the time is 1-60 min. Preferably, the organic solvent comprises methanol, ethanol, acetic acid, tetrahydrofuran or ethyl acetate; The second catalyst comprises a palladium on carbon catalyst, palladium-silica, palladium-alumina, platinum on carbon catalyst, raney nickel, nickel-silica, or nickel on carbon catalyst. Preferably, the molar ratio of the diallyl malonate to the hydrogen is 1:2-6. Preferably, the hydrogenation reaction is carried out in a fixed bed; The temperature of the hydrogenation reaction is 20-180 ℃, the pressure is