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CN-122010829-A - Method for preparing 2-aminopyridine compounds based on dearomatization-aromatization strategy

CN122010829ACN 122010829 ACN122010829 ACN 122010829ACN-122010829-A

Abstract

The application discloses a method for preparing 2-aminopyridine compounds based on a dearomatization-aromatization strategy, belonging to the technical field of organic synthesis. Pyridine is firstly dearomatized under the mediation of DMAD/isonitrile acid ester, and then is rearomatized under the action of alkali, so that direct amination of pyridine ortho-position C-H bond can be realized with high selectivity, and the 2-aminopyridine compound is obtained. The preparation method does not need metal catalysis or pre-activation of pyridine, all reagents are common reagents, and the preparation method is simple to operate and high in yield. The obtained product 2-aminopyridine compound has wide application prospect in medicine, agriculture, materials and chemical synthesis.

Inventors

  • HAN XIAOLI
  • CAI JIANGTAO
  • CHEN SHUAIYU
  • SONG BINGRU

Assignees

  • 浙江师范大学

Dates

Publication Date
20260512
Application Date
20260413

Claims (10)

  1. 1. A method for preparing 2-aminopyridine compounds based on a dearomatization-aromatization strategy, comprising: Slowly adding dimethyl butynedioate into a mixed solution containing pyridine compounds shown in a formula 1, isonitrile acid ester compounds shown in a formula 2 and a solvent, and reacting under stirring to obtain a solution containing an intermediate; Adding an alkali reagent into the solution containing the intermediate, and carrying out reaction II under stirring to obtain the 2-aminopyridine compound with the structure shown in the formula 3; The method comprises the steps of (1), The method comprises the steps of (2), Formula 3; Wherein R 1 is selected from one of hydrogen, halogen, alkyl, cyano and acetyl, and R 2 is alkyl or aryl; The reaction formulas of the reaction I and the reaction II are shown in a formula 4, wherein INT is an intermediate; Formula 4.
  2. 2. The method according to claim 1, wherein when R 1 is hydrogen, the substituent R 2 is selected from one of 2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3, 5-dimethylphenyl, 3, 4-difluorophenyl, allyl, cyclohexyl, cyclopentyl, isopropyl, n-octyl.
  3. 3. The method of claim 1, wherein when R 2 is 2-bromophenyl, R 1 is halogen, wherein halogen is selected from one of fluorine, chlorine, bromine, and iodine, and the substitution position of halogen is a pyridine meta position.
  4. 4. The method of claim 1, wherein when R 1 is alkyl, the alkyl is ethyl or t-butyl, wherein the ethyl substitution is at the para-position relative to the pyridine, and the t-butyl substitution is at the para-position relative to the pyridine.
  5. 5. The method of claim 1, wherein when R 1 is cyano, the substitution position of cyano is para to pyridine.
  6. 6. The method of claim 1, wherein when R 1 is acetyl, the substitution position of the acetyl group is a pyridine meta position.
  7. 7. The method according to claim 1, wherein the 2-aminopyridine-based compound is selected from compounds of one structure of formulae 3a to 3 u: 。
  8. 8. the method according to claim 1, wherein the solvent is at least one selected from toluene, tetrahydrofuran, acetonitrile, N-dimethylformamide, dimethyl sulfoxide.
  9. 9. The method according to claim 1, wherein the base reagent is selected from at least one of triethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate.
  10. 10. The method according to claim 1, wherein the molar ratio of the pyridine compound represented by formula 1 to the isonitrile acid ester compound represented by formula 2 is 1:1 to 1:2; The dosage ratio of the pyridine compound shown in the formula 1 to the solvent is 1mmol:1.5 mL-1 mmol:4mL; the molar ratio of the pyridine compound shown in the formula 1 to the dimethyl butynedioate is 1:1-1:2; the molar ratio of the pyridine compound shown in the formula 1 to the alkali reagent is 1:1-1:2; the reaction I conditions comprise that the reaction time is 2-36 h; The reaction II is carried out under the conditions that the reaction temperature is 30-120 ℃.

Description

Method for preparing 2-aminopyridine compounds based on dearomatization-aromatization strategy Technical Field The application relates to a method for preparing 2-aminopyridine compounds based on a dearomatization-aromatization strategy, belonging to the technical field of organic synthesis. Background Pyridine is an important nitrogen-containing aromatic heterocycle and widely exists in natural products, drug molecules, functional materials and the like. The selective modification of the pyridine C-H bond can significantly improve the functional diversity, so that the research on the selective functionalization of the pyridine C-H bond is always one of the research hot spots of great interest in the field of organic synthesis. Among them, 2-aminopyridine is one of the most common pyridine-substituted molecules in small drug molecules, and is considered to be the primitive fragment with the simplest structure for synthesizing active heterocyclic molecules. For example, ipratropium (Isopropiram) for the treatment of neuropathic pain, tenoxicam (Tenoxicam) for the relief of non-inflammatory pain, tubulin polymerization inhibitors (ABT-751), CFTR protein modulators Lu Maka torr (Lumacaftor), and the like. In addition, the pyridine nitrogen atom and the amino group in the 2-aminopyridine have nucleophilicity, are often used as important reaction precursors in organic synthesis, are used for preparing heterocyclic structures such as pyridine imidazole, pyridine triazole and the like, and are important building blocks for constructing nitrogen-containing complex molecules. At present, a method for constructing 2-aminopyridine through direct amination of pyridine ortho-position C-H bond mainly uses pyridine N-oxide or pyridine salt as a reactant, and the method needs to preactivate pyridine. The synthesis method for realizing the 2-aminopyridine directly through the ortho-C-H bond of the pyridine without pre-activation is quite limited. Therefore, it is important to explore how to simply and efficiently construct 2-aminopyridine through direct amination of an unactivated pyridine ortho-position C-H bond. Disclosure of Invention In order to solve the problems of complex synthesis process and low efficiency caused by the need of preactivation and metal participation in the prior art of 2-aminopyridine compounds, the application provides a technical scheme for preparing the 2-aminopyridine compounds based on a dearomatization-aromatization strategy, and under the conditions of no metal participation and no need of preactivation, the direct amination of pyridine ortho-C-H bonds is realized through the dearomatization and alkali-promoted rearomatization process mediated by dimethyl butynedioate (DMAD)/isonitrile ester, and the 2-aminopyridine compounds are efficiently constructed. The application adopts the following technical scheme: according to a first aspect of the present application there is provided a process for the preparation of 2-aminopyridine compounds based on a dearomatization-aromatization strategy comprising: Slowly adding dimethyl butynedioate into a mixed solution containing pyridine compounds shown in a formula 1, isonitrile acid ester compounds shown in a formula 2 and a solvent, and reacting under stirring to obtain a solution containing an intermediate; Adding an alkali reagent into the solution containing the intermediate, and carrying out reaction II under stirring to obtain the 2-aminopyridine compound with the structure shown in the formula 3; The method comprises the steps of (1), The method comprises the steps of (2),Formula 3; Wherein R 1 is selected from one of hydrogen, halogen, alkyl, cyano and acetyl, and R 2 is alkyl or aryl; The reaction steps and the reaction formulas of the reaction I and the reaction II are shown in a formula 4, wherein INT is an intermediate; Formula 4. Optionally, when R 1 is hydrogen, the substituent R 2 is selected from one of 2-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3, 5-dimethylphenyl, 3, 4-difluorophenyl, allyl, cyclohexyl, cyclopentyl, isopropyl, n-octyl. Optionally, when R 2 is 2-bromophenyl, R 1 is halogen, wherein halogen is selected from one of fluorine, chlorine, bromine and iodine, and the substitution position of halogen is pyridine meta position. Alternatively, when R 1 is alkyl, the alkyl is ethyl or tert-butyl, wherein the substitution position of the ethyl is the meta-position of pyridine and the substitution position of the tert-butyl is the para-position of pyridine. Alternatively, when R 1 is cyano, the substitution position of cyano is pyridine para. Alternatively, when R 1 is acetyl, the substitution position of the acetyl is pyridine para. Optionally, the 2-aminopyridine compound is selected from compounds with one structure in the formulas 3 a-3 u: 。 Optionally, the solvent is selected from at least one of toluene, tetrahydrofuran, acetonitrile, N-dimethylformamide and dimethyl sulfoxide. Opt