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CN-121974864-A - Alkyluracil derivative, and preparation method and application thereof

CN121974864ACN 121974864 ACN121974864 ACN 121974864ACN-121974864-A

Abstract

The invention provides an alkyl uracil derivative, a preparation method and application thereof, and relates to the technical field of organic synthesis, comprising the following steps of carrying out hydrogenation alkylation reaction on uracil analogues and olefin under the action of an iron catalyst and a hydrogen source to obtain the alkyl uracil derivative; the iron catalyst comprises at least one of ferric nitrate nonahydrate, ferrous nitrate, ferric chloride, ferrous chloride, ferric sulfate and ferric oxalate, and the hydrogen source comprises at least one of sodium borohydride, lithium aluminum hydride, triphenyl silicon, triethyl silicon and borane. According to the invention, olefin is used as an alkyl raw material, no pre-functionalization is needed, and a specific catalyst and a specific hydrogen source are combined to successfully realize the hydroalkylation reaction of olefin and uracil analogues, so that the technical effect of constructing a series of alkyl uracil derivatives is achieved. The invention can react at room temperature without light and heat conditions, has short reaction time and better functional group tolerance.

Inventors

  • WU JUANJUAN
  • WANG LEILEI
  • HOU YI
  • SUN YAN
  • WANG JINGHE
  • YANG YULIANG

Assignees

  • 德州学院

Dates

Publication Date
20260505
Application Date
20260127

Claims (10)

  1. 1. A process for the preparation of an alkyluracil derivative, comprising the steps of: carrying out hydrogenation alkylation reaction on uracil analogues and olefin under the action of an iron catalyst and a hydrogen source to obtain the alkyl uracil derivative; the iron catalyst comprises at least one of ferric nitrate nonahydrate, ferrous nitrate, ferric chloride, ferrous chloride, ferric sulfate and ferric oxalate; the hydrogen source includes at least one of sodium borohydride, lithium aluminum hydride, triphenylsilicon, triethylsilicon, and borane.
  2. 2. The method of claim 1, wherein the uracil analog is a pharmaceutically active group containing uracil having the structure: ; R 1 is selected from hydrogen, benzyl, naphtyl, alkyl, alkenyl-substituted alkyl, alkynyl-substituted alkyl, or ester-substituted alkyl; R 2 is selected from hydrogen, benzyl, naphtyl, alkyl, alkenyl-substituted alkyl, alkynyl-substituted alkyl, or ester-substituted alkyl.
  3. 3. The method of producing according to claim 1, wherein the olefin comprises at least one of a cyclic olefin and a chain olefin; Preferably, the cyclic olefin comprises at least one of cyclohexene, cyclopentene, and cyclooctene; preferably, the chain olefin includes at least one of hexene, halogen substituted olefin, alcohol substituted olefin, ester substituted olefin, ether substituted olefin, and phenyl substituted olefin.
  4. 4. A method of preparation according to any one of claims 1 to 3, wherein the iron catalyst is ferric nitrate nonahydrate; preferably, the hydrogen source is sodium borohydride; Preferably, the solvent used in the hydroalkylation reaction comprises at least one of ethanol, acetonitrile, methylene chloride, dimethyl sulfoxide, N-dimethylformamide, and N, N-dimethylacetamide; preferably, the solvent is a mixed solvent of ethanol and acetonitrile; preferably, the volume ratio of the ethanol to the acetonitrile is 1:1.
  5. 5. The method of any one of claims 1-3, wherein the uracil analog to olefin feed molar ratio is 1:1-9; preferably, the uracil analog to olefin feed molar ratio is 1:3.
  6. 6. The preparation method of claim 5, wherein the uracil analog and the iron catalyst are added in a molar ratio of 1:1-9; preferably, the uracil analog is fed in a molar ratio to the iron catalyst of 1:4.
  7. 7. The method of claim 6, wherein the uracil analog is added to the hydrogen source in a molar ratio of 1:1-9; preferably, the uracil analog is fed in a molar ratio to the hydrogen source of 1:4.
  8. 8. The method according to claim 7, wherein the hydroalkylation reaction is carried out at a temperature of 20 ℃ to 30 ℃ for a time of 0.1h to 3h.
  9. 9. An alkyluracil derivative, characterized by being produced by the production method according to any one of claims 1 to 8; the alkyl uracil derivative has the following structure: 。
  10. 10. use of an alkyluracil derivative according to claim 9 in the manufacture of a medicament.

Description

Alkyluracil derivative, and preparation method and application thereof Technical Field The invention relates to the technical field of organic synthesis, in particular to an alkyl uracil derivative, and a preparation method and application thereof. Background Olefins (such as ethylene, propylene, butadiene and the like) are core products of petrochemical industry, the annual output of the olefins exceeds one hundred million tons, the olefins are basic monomers of high polymer materials such as plastics, rubber, fibers and the like, and are important active molecular frameworks, and carbon-carbon double bonds widely exist in natural products (such as terpenes and steroids) and drug molecules, such as artemisinin (antimalarial drugs) and taxol (anticancer drugs), and the natural products comprise olefin structures. Olefins are also organically synthesized "transformers" that convert simple double bonds into innumerable functional molecules ranging from plastics to drugs, from fuels to liquid crystals, through a diverse reaction type. The reactivity and the modifiable nature of olefins make them an indispensable tool for the construction of complex molecules by chemists. Nitrogen-containing heterocycles are the core groups of numerous natural and synthetic compounds, and are widely found in pharmaceutical and functional material systems. Uracil has received great attention as an important class of nitrogen-containing aromatic heterocyclic compounds exhibiting significant biological activity in a number of pharmacological dimensions. Various important bioactive molecules and clinical drugs have been shown to contain uracil structures such as diclazuril (diclazuril), c-Met kinase inhibitors, 5-HT1A receptor modulators, 6-azauridine (antiviral agents), herpes simplex virus inhibitors, antibacterial agents, HIV-1 reverse transcriptase inhibitors, interleukin-5 inhibitors, and TAM kinase inhibitors. In view of the wide application and important value of uracil, the structure of uracil is effectively modified, and the uracil has important significance in expanding the application range and improving the pharmaceutical activity. The uracil is modified by olefin, so that the pharmaceutical activity of the uracil can be improved, and the product is possible to be applied to the pharmaceutical field. In recent years, uracil alkylation reactions have progressed rapidly, most of the alkyl precursors have complex structures, and hydroalkylation reactions involve fewer reactions. In view of this, the present invention has been made. Disclosure of Invention The invention aims to provide a preparation method of an alkyl uracil derivative, which uses olefin as an alkyl raw material, does not need to be functionalized, adopts a specific catalyst and a hydrogen source in a combined way, has mild reaction conditions and short time, successfully realizes the hydroalkylation reaction of olefin and uracil analogues, and achieves the technical effect of constructing a series of alkyl uracil derivatives. It is another object of the present invention to provide an alkyluracil derivative. The invention also aims to provide an application of the alkyl uracil derivative, which is beneficial to improving the preparation effect of the medicine. In order to achieve the above object of the present invention, the following technical solutions are specifically adopted: In a first aspect, a process for preparing an alkyluracil derivative, comprising the steps of: carrying out hydrogenation alkylation reaction on uracil analogues and olefin under the action of an iron catalyst and a hydrogen source to obtain the alkyl uracil derivative; the iron catalyst comprises at least one of ferric nitrate nonahydrate, ferrous nitrate, ferric chloride, ferrous chloride, ferric sulfate and ferric oxalate; the hydrogen source includes at least one of sodium borohydride, lithium aluminum hydride, triphenylsilicon, triethylsilicon, and borane. Further, the uracil analog is uracil containing a drug active group and has the following structure: ; R 1 is selected from hydrogen, benzyl, naphtyl, alkyl, alkenyl-substituted alkyl, alkynyl-substituted alkyl, or ester-substituted alkyl; R 2 is selected from hydrogen, benzyl, naphtyl, alkyl, alkenyl-substituted alkyl, alkynyl-substituted alkyl, or ester-substituted alkyl. Further, the olefin includes at least one of a cyclic olefin and a chain olefin; Preferably, the cyclic olefin comprises at least one of cyclohexene, cyclopentene, and cyclooctene; preferably, the chain olefin includes at least one of hexene, halogen substituted olefin, alcohol substituted olefin, ester substituted olefin, ether substituted olefin, and phenyl substituted olefin. Further, the iron catalyst is ferric nitrate nonahydrate; preferably, the hydrogen source is sodium borohydride; preferably, the solvent used in the hydroalkylation reaction comprises at least one of ethanol, acetonitrile, dichloromethane, dimethyl sulfoxide, N-dimethylformamide