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CN-121991065-A - Method for preparing 1, 3-dithio indolizine compound without catalyst and application thereof

CN121991065ACN 121991065 ACN121991065 ACN 121991065ACN-121991065-A

Abstract

The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a method for preparing a1, 3-dithioindolizine compound without a catalyst and application thereof. In an organic solvent, taking substituted 2-methylpyridine, alpha-bromoketone and N-thiosuccinimide as raw materials, and carrying out reflux stirring reaction to obtain the 1, 3-dithioindolizine compound. The method does not need to use a metal catalyst and a chemical oxidant, has mild reaction conditions, accords with the green chemical principle, and has the characteristics of simple operation, high yield, good functional group compatibility and the like. Meanwhile, cell experiment results show that the 1, 3-dithioindolizine compound provided by the invention has better inhibition activity on mycobacterium tuberculosis standard strains, sensitive strains and drug-resistant strains, and provides drug lead compounds and drug candidates for development of novel antituberculosis drugs, thereby having important significance in preventing and/or treating tuberculosis.

Inventors

  • LIU GONGQING
  • LI XIN
  • WU DONGFANG
  • MA HUIXIANG
  • TAO RUIJIE
  • LU TIANQI
  • SHEN JIANZENG
  • LING YONG

Assignees

  • 南通大学

Dates

Publication Date
20260508
Application Date
20260130

Claims (9)

  1. 1. A method for preparing a1, 3-dithioindolizine compound without a catalyst is characterized in that 2-methylpyridine shown in a formula (I), alpha-bromoketone shown in a formula (II) and N-thiosuccinimide shown in a formula (III) are taken as raw materials in an organic solvent, and the raw materials are subjected to reflux reaction to obtain the 1, 3-dithioindolizine compound shown in a formula (IV), wherein the reaction equation is shown as follows: , Wherein the substituent R 1 is hydrogen atom, halogen, C 1 -C 10 alkyl and alkoxy, R 2 is phenyl, naphthyl and phenyl substituted by one or more substituents, wherein the substituents are alkoxy, alkyl and halogen, R 3 is C 1 -C 10 alkyl, 3-6 carbocyclalkyl, naphthyl, furyl, phenyl and phenyl with one substituent, wherein the substituents are halogen, alkyl, alkoxy and cyano.
  2. 2. The method for preparing a1, 3-dithioindolizine compound without a catalyst according to claim 1, wherein the molar ratio of the 2-methylpyridine of the structure shown in the formula (I), the alpha-bromoketone of the structure shown in the formula (II) and the N-thiosuccinimide of the structure shown in the formula (III) is 1:1:2-3.
  3. 3. The method for preparing a 1, 3-dithioindolizine compound without catalyst according to claim 2, wherein the molar ratio of the 2-methylpyridine of the structure of formula (I), the α -bromoketone of the structure of formula (II) and the N-thiosuccinimide of the structure of formula (III) is 1:1:3.
  4. 4. The method for preparing a 1, 3-dithioindolizine compound without catalyst according to claim 1, wherein the organic solvent is selected from one of 1, 2-dichloroethane, 1, 4-dioxane, toluene, N-dimethylformamide or dimethylsulfoxide.
  5. 5. The method for preparing a1, 3-dithioindolizine compound without catalyst according to claim 1, wherein the reflux reaction temperature is 90 ℃ and the reaction time is 4-10 hours.
  6. 6. The method for preparing the 1, 3-dithioindolizine compound without the catalyst according to claim 1 is characterized in that the mixture is concentrated under reduced pressure after stirring reaction, and is separated by column chromatography, petroleum ether/ethyl acetate mixed solution is used as an eluent, wherein the volume ratio of petroleum ether to ethyl acetate is 30-10:1.
  7. 7. A pharmaceutical composition comprising a1, 3-dithioindolizine compound, a pharmaceutically acceptable salt, solvate or hydrate thereof, prepared according to the method of claim 1, and a pharmaceutically acceptable carrier or adjuvant.
  8. 8. Use of a pharmaceutical composition according to claim 7 for the preparation of a medicament for the prevention and/or treatment of tuberculosis.
  9. 9. The use of a pharmaceutical composition according to claim 8, wherein the mycobacterium tuberculosis comprises a standard strain of mycobacterium tuberculosis, a susceptible strain of mycobacterium tuberculosis or a resistant strain of mycobacterium tuberculosis.

Description

Method for preparing 1, 3-dithio indolizine compound without catalyst and application thereof Technical Field The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a method for preparing a1, 3-dithioindolizine compound without a catalyst and application thereof. Background Indolizine is a nitrogen-containing heterocyclic compound formed by fusing six-membered and five-membered rings, which is widely found in natural products, fluorescent materials, and numerous molecules with biological activity, including anticancer drugs, antitubercular drugs, antimalarial drugs, apoptosis inducers, and antifungal drugs. The compound has been receiving attention because of its anti-inflammatory, antibacterial, antioxidant and other biological activities. Organosulfur compounds have been attracting attention in synthetic chemistry because of their versatility, and they are not only key intermediates in complex molecular construction, but are also often used widely as high-efficiency catalysts. Sulfur atoms, when combined with heterocyclic ring systems, tend to confer substantial biological activity to the molecule, with sulfur-containing modified indolizines being a class of biologically active molecules with significant potential. Therefore, the study of skeleton construction and functional group modification of the thioether-functionalized indolizine compound has important value in the synthesis method, provides a new chemical space for drug discovery and development, and has profound scientific significance and application prospect. In the last few decades, the synthesis of 1, 3-dithioindolizine compounds has been mainly dependent on the introduction of sulfur-containing groups on the pre-built indolizine skeleton. Common strategies include the use of transition metal catalyzed cross-coupling reactions to effect thioetherification, or the activation of a thio reagent with the help of an oxidant, followed by electrophilic sulfide modification of the indolizine structure. However, these methods mostly rely on expensive noble metal catalysts or oxidizing agents that have adverse environmental effects, and remain limited in terms of sustainability and economy. Disclosure of Invention The invention provides a method for directly synthesizing a1, 3-dithioindolizine compound from 2-methylpyridine, alpha-bromoketone and N-thiosuccinimide under the condition of no catalyst and application thereof, one of the purposes of the invention is to provide a1, 3-dithioindolizine compound, the other purpose of the invention is to provide a method for preparing and purifying the 1, 3-dithioindolizine compound, and the third purpose of the invention is to apply the 1, 3-dithioindolizine compound to prepare a medicament for preventing and/or treating tuberculosis. The above object of the present invention is achieved by the following technical solutions: in an organic solvent, carrying out reflux reaction on 2-methylpyridine shown in a formula (I), alpha-bromoketone shown in a formula (II) and N-thiosuccinimide shown in a formula (III) serving as raw materials at a certain temperature to obtain a1, 3-dithioindolizine compound shown in a formula (IV), wherein the reaction equation is shown as follows: , Wherein the substituent R 1 is hydrogen atom, halogen, C 1-C10 alkyl and alkoxy, R 2 is phenyl, naphthyl and phenyl substituted by one or more substituents, wherein the substituents are alkoxy, alkyl and halogen, R 3 is C 1-C10 alkyl, 3-6 carbocyclalkyl, naphthyl, furyl, phenyl and phenyl of one substituent, and the substituents are halogen, alkyl, alkoxy and cyano. The molar ratio of the 2-methylpyridine of the structure shown in the formula (I), the alpha-bromoketone of the structure shown in the formula (II) and the N-thiosuccinimide of the structure shown in the formula (III) is 1:1:2-1:1:3, preferably 1:1:3. The organic solvent is one or more of 1, 2-dichloroethane, 1, 4-dioxane, toluene, DMF and DMSO, preferably 1, 2-dichloroethane. The reflux reaction is carried out at 90 ℃ for 4-10 h. After the reaction is finished, the reaction solution is decompressed and concentrated, the concentrate is separated by column chromatography, the mixed solution of petroleum ether and ethyl acetate is used as eluent, the volume ratio of petroleum ether to ethyl acetate is (30-10): 1, the eluent is collected, and the solvent is distilled off in a rotary way to obtain the 1, 3-dithioindolizine compound shown in the formula (IV). The 1, 3-dithioindolizine compound and pharmaceutically acceptable salts, solvates or hydrates thereof have antituberculosis activity. The compound has obvious bactericidal/bacteriostatic activity on standard strain, sensitive strain and drug-resistant strain of mycobacterium tuberculosis. In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient selected from any one or more of the foregoing 1, 3-di