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CN-121974886-A - Arylcarboxypyrazole compound and synthesis method thereof

CN121974886ACN 121974886 ACN121974886 ACN 121974886ACN-121974886-A

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to an aryl formyl pyrazole compound and a synthesis method thereof, wherein the synthesis method comprises the steps of uniformly dispersing an aryl formic acid compound shown in a formula 1 and a pyrazole alcohol compound shown in a formula 2 in an organic solvent, stirring at room temperature, sequentially adding an organic base and an onium salt condensing agent, so that the aryl formyl pyrazole compound can be efficiently prepared, the yield of a target compound is up to 93%, and a drug molecular prodrug or a compound with potential biological activity is obtained by modifying hydroxyl on a pyrazole ring. Meanwhile, the invention effectively overcomes the technical defects of severe reaction conditions such as acetone cyanohydrin, trimethyl cyanosilane and the like which are extremely toxic tube products in the prior rearrangement technology, and solves the limitation of complex range of substrate synthesis.

Inventors

  • GAN XIUHAI
  • ZHANG MEI
  • HE JIANGQIN
  • LIU LI
  • WANG LINGLING
  • CHEN QIQI

Assignees

  • 贵州大学

Dates

Publication Date
20260505
Application Date
20260126

Claims (7)

  1. 1. The synthesis method of the arylformylpyrazole compound is characterized by comprising the following steps of: sequentially adding an arylformic acid compound shown in a formula 1 and a pyrazole alcohol compound shown in a formula 2 into a reaction container, uniformly dispersing the arylformic acid compound and the pyrazole alcohol compound in an organic solvent, stirring the mixture at room temperature, and sequentially adding an organic base and an onium salt condensing agent to generate an arylformylpyrazole compound shown in a formula 3; the synthetic route is as follows: in the above-mentioned reaction scheme, the reaction mixture, Represents a C 6-20 aromatic ring or a C 3-20 heteroaromatic ring, wherein the heteroatoms are selected from N, O or S; m is selected from the integers of 0,1,2 and 3, R represents substituents on the ring, each R is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-20 aryl, C 3-20 heteroaryl, phenoxy, thio and nitro, wherein the heteroatom in the heteroaryl is selected from N, O or S; R ' is selected from C 1-6 alkyl, C 1-6 cycloalkyl, R ' ' is selected from hydrogen, C 1-6 alkyl, trifluoromethyl; Wherein the condensing agent is an onium salt condensing agent.
  2. 2. The method for synthesizing an arylformylpyrazole compound according to claim 1, wherein, Represents a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a quinoxaline ring, a quinoline ring, an isoquinoline ring, a naphthyridine ring, a phenanthrene Luo Linhuan, a benzene ring, a cinnoline ring, a benzopyran ring, or a pyran ring; R represents Each R is independently selected from one or two of hydrogen, chlorine, bromine, fluorine, methyl, methoxy, phenyl, phenoxy, substituted phenyl, nitro and methylthio, wherein the substitution is complete substitution by at least one of hydrogen, fluorine, chlorine, bromine, iodine, nitro and isopropyl sulfonyl; R ' is selected from methyl, ethyl, propyl, cyclopropyl, butyl, cyclobutyl, and R ' ' is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, trifluoromethyl.
  3. 3. The method for synthesizing the arylformylpyrazole compound according to claim 1 or 2, wherein the organic solvent is selected from one or more solvents selected from methanol, ethanol, tert-butanol, isopropanol, acetonitrile, ethyl acetate, toluene, tetrahydrofuran, toluene, propanol, chlorobenzene, trifluoromethylbenzene, dichloromethane, dichloroethane, and DMF.
  4. 4. The method for synthesizing the arylformylpyrazole compound according to claim 1 or 2, wherein the onium salt condensing agent is at least one selected from tetramethylchlorourea hexafluorophosphate (TCFH), tetramethylfluorourea hexafluorophosphate (TFFH), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tripyrrolidinylphosphine (PyBOP), 2- (7-azabenzotriazol) -N, N' -tetramethylurea Hexafluorophosphate (HATU), O-benzotriazol-tetramethylurea Hexafluorophosphate (HBTU), and the organic base is N-methylimidazole (NMI) or N-methylmorpholine (NMM).
  5. 5. The method for synthesizing an arylformylpyrazole compound according to claim 1 or 2, wherein the reaction temperature is rt-70 ℃.
  6. 6. The method for synthesizing the arylformylpyrazole compound according to claim 1 or 2, wherein the molar ratio of the compound of formula 1 to the compound of formula 2 is 1:1-1.25, and the molar ratio of the onium salt condensing agent to the organic base is 1.25:1.2-3.2.
  7. 7. The method for synthesizing the arylformylpyrazole compound according to claim 1 or 2, wherein the purification treatment comprises the steps of standing the reaction solution overnight after the reaction is completed so as to precipitate the target compound, filtering, washing with petroleum ether, drying, concentrating the organic phase under reduced pressure to obtain a residue if no solid is precipitated, and separating the residue by silica gel column chromatography to obtain the target product shown in formula 3.

Description

Arylcarboxypyrazole compound and synthesis method thereof Technical Field The invention relates to the technical field of organic synthesis, in particular to an aryl formyl pyrazole compound and a synthesis method thereof. Background The arylformylpyrazole compounds have wide pharmaceutical applications. For example, in 1979, JP54009279A discloses that pyrazolylpyridones have better herbicidal activity, in 2004, WO2004033431A2 discloses that heterocyclic compounds such as pyridine, pyrazine, pyrimidine, pyridazine and the like with an arylformylpyrazole structure can be used as nicotinic acid receptor agonists for preventing and treating metabolic related diseases, in 2005, the Zhengda company in WO2005058037A1 discloses that pyridine heterocyclic compounds with an arylformylpyrazole structure are used as effective herbicides, and in 2018, qingdao compound Co Ltd, CN107674025A discloses that 4-benzoyl pyrazole compounds have excellent post-emergence herbicidal activity and crop compatibility. Meanwhile, the arylformylpyrazole compound is also an important drug and an intermediate for organic synthesis, and is widely applied to synthesis of drugs and fine chemical products. For the synthesis of aryl formyl pyrazoles compounds, the prior art generally adopts an esterification-rearrangement two-step reaction, wherein the esterification is catalyzed by an acyl chloride method or a condensing agent (DCC, CMPI and the like), and the rearrangement is catalyzed by acetone cyanohydrin, alCl 3, trimethylcyanosilane or the like. However, these methods have problems of low yield (10-50%) and high risk of catalyst/solvent, such as only 20-50% of target compound obtained by acetone cyanohydrin (highly toxic tube product) in the literature (J. Agric. Food chem. 2015, 63, 5587-5596), only 10-30% of target compound obtained by trimethyl cyanosilane (highly toxic, explosive, hydrocyanic acid released upon water) in the literature (J. Agric. Food chem. 2023, 71, 3950-3959), and difficult process scale-up by using AlCl 3 (toxic, corrosive chemical) as a solvent in the literature (Molecular diversity. 2020, 24, 1025-1042). Therefore, the development of the method for preparing the aryl formyl pyrazole compound has important significance, and is safe, efficient, simple and convenient to operate and good in universality. Disclosure of Invention The invention aims to provide a novel synthesis method of aryl formyl pyrazole compounds. According to the invention, arylcarboxylic acid and pyrazole alcohol compounds are taken as raw materials, dispersed in a reaction solvent, stirred at room temperature, and sequentially added with organic base and onium salt condensing agent, so that the arylformyl pyrazole compounds can be efficiently prepared, the yield of target compounds is up to 93%, and hydroxy groups on pyrazole rings can be further functionalized, so that a drug molecular prodrug or a compound with potential biological activity can be obtained. The synthesis method is simple and easy to operate, the synthesis conditions are mild, the synthesis method has wide substrate universality and good substituent tolerance, the separation and purification process is simple to operate, and the target compound can be produced in good to excellent yield. The invention realizes two steps of esterification and rearrangement under one-step condensation condition for the first time, effectively shortens the reaction steps, greatly improves the atom economy and obviously reduces the preparation cost. Meanwhile, the invention effectively overcomes the technical defects of severe reaction conditions such as acetone cyanohydrin, trimethyl cyanosilane and the like which are extremely toxic tube products in the prior rearrangement technology, and the limitation of complex range of substrate synthesis and the like, thereby being a general synthesis strategy with safe production, economy and high efficiency. The invention provides a synthesis method of an aryl formyl pyrazole compound, which comprises the following steps: Sequentially adding the compounds shown in the formulas 1 and 2 into a reaction container, uniformly dispersing the compounds in an organic solvent, stirring the mixture at room temperature, and sequentially adding an organic base and an onium salt condensing agent to generate an arylformylpyrazole compound shown in the general formula; The synthetic route is shown in the following reaction formula: In the above reaction formula, the compound represents a C 6-20 aromatic ring and a C 3-20 heteroaromatic ring, wherein the heteroatom is selected from N, O or S; m is selected from the integers of 0,1,2 and 3, R represents substituents on the ring, each R is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 6-20 aryl, C 3-20 heteroaryl, phenoxy, thio and nitro, wherein the heteroatom in the heteroaryl is selected from N, O or S; R ' is selected from C 1-6 alkyl, C 1-6 cycloalkyl, R ' ' is selected from hydrogen,