Deoxidized halofuginone compound and preparation method and application thereof

A technology for halofuginone and compound, which is applied in the field of deoxyhalofuginone compound and its preparation, can solve the problem of not finding a targeted bacterial type ProRS and the like, and achieves the effects of good development prospects, cheap and easy-to-obtain raw materials, and high yield.

Active Publication Date: 2019-01-04
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

So far, no antibacterial drugs targeting bacterial ProRS have been found

Method used

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  • Deoxidized halofuginone compound and preparation method and application thereof
  • Deoxidized halofuginone compound and preparation method and application thereof
  • Deoxidized halofuginone compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Preparation of (R)-3-butyl-2-(3-bromo-2-propionyl)piperidine-1-carboxylate (compound 23)

[0034] Piperidine (100mmol), NCS (111.6mmol) was rapidly stirred in ether (500mL), and reacted at room temperature for 4h. After the reaction was complete, the residue was removed by filtration, and the filtrate was concentrated at room temperature to about 80 mL, then added dropwise to potassium hydroxide (100 mmol) in ethanol (50 mL) in an ice bath, reacted overnight, and filtered to obtain filtrate A. Sodium hydroxide (150mmol) and ethyl acetoacetate (100mmol) were dissolved in solvent water, heated at 50°C for 4h, and stirred overnight at room temperature to obtain B. A and B were mixed and refluxed for 4h to obtain a yellow solution. It was extracted with dichloromethane (3×75 mL), the organic phase was dried over anhydrous magnesium sulfate, and the organic solvent was removed under reduced pressure to obtain a crude product. The crude product was stirred with di...

Embodiment 2

[0035] The preparation of embodiment 2 deoxyhemoshenone compound (compound 1-15)

[0036] Compound 23 (2mmol), the corresponding substituted quinazolinone (2mmol), potassium carbonate (6mmol) were reacted in the solvent DMF (5mL) for 2-8h. The reaction was detected by TLC. After the reaction was complete, excess water was added, and a solid was precipitated at room temperature. Intermediate D was obtained by suction filtration. Intermediate D was dissolved in 1,4-dioxane (3 mL), and concentrated hydrochloric acid was added dropwise at room temperature for 4-6 days. Detected by TLC, after the reaction was complete, the organic solvent was removed under reduced pressure. The mobile phase (dichloromethane:methanol (v / v)=1:7) was passed through a silica gel column to obtain compound 1-15 with a yield of about 75-90%.

Embodiment 3

[0037] The preparation of embodiment 3 deoxyhemoshenone compound (compound 16)

[0038]Compound 2 (2mmol) and sodium borohydride (2mmol) were reacted in methanol (2mL) on ice for 1h. The progress of the reaction was detected by TLC. After the reaction was complete, the organic solvent was removed under reduced pressure. The mobile phase (dichloromethane: methanol (v / v) = 1:6) was passed through a silica gel column to obtain compound 16. Its yield is about 100%.

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PUM

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Abstract

The invention provides a deoxidized halofuginone compound. A structural formula of the deoxidized halofuginone compound is as shown in the specification, wherein R1 refers to a halogen radical or hydrogen; R2 refers to hydrogen, a halogen radical, C1-C3 alkyl, C1-C3 alkoxy or trifluoromethyl; R3 refers to hydrogen, a halogen radical, C1-C3 alkyl, C1-C3 alkoxy or trifluoromethyl; X1 or X2 refers tonitrogen or carbon; Y refers to hydrogen, hydroxyl or carbonyl. The synthetic deoxidized halofuginone compound with piperidine as a raw material has advantages of cheapness and easiness in acquisition of the raw material, simplicity and easiness in operation of a synthesis method, high yield and product stability. The deoxidized halofuginone compound has great inhibiting effects on Gram positive(Gram<+>) and Gram negative (Gram<->) and has a promising application prospect in treatment of human and poultry bacterial infection.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically relates to a deoxyhemoshenone compound and its preparation method and application. Background technique [0002] The advent of penicillin in the 1940s ushered humans into the era of antibiotics, and anti-infective treatment entered a new era, and the fatality rate of infectious diseases was greatly reduced. For half a century, humans have been using antimicrobials as the most powerful weapon for anti-infection treatment. However, with the widespread use of antibacterial drugs, bacteria have developed resistance to antibiotics. Some strains have also developed cross-resistance, such as Staphylococcus aureus, Streptococcus pneumoniae, Salmonella and Mycobacterium tuberculosis, and these strains cannot find suitable therapeutic drugs. In recent years, drug-resistant bacteria are spreading rapidly, seriously threatening human health and safety. Therefore, it is imminent to d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06A61P31/04
CPCA61P31/04C07D403/06
Inventor 周晖皓程宝顾琼徐峻
Owner SUN YAT SEN UNIV
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