Pleuromutilin derivative with 2-aminothiophenol and 1,2,3-triazole side chain, preparation and application

A technology of aminobenzenethiol and pleuromutilin, applied in medical preparations containing active ingredients, organic chemistry, organic active ingredients, etc., can solve the problem of rare drug-resistant bacteria

Active Publication Date: 2019-10-25
SOUTH CHINA AGRI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005]Since the mechanism of action of pleuromutilin compounds is different from that of antibiotics wi

Method used

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  • Pleuromutilin derivative with 2-aminothiophenol and 1,2,3-triazole side chain, preparation and application
  • Pleuromutilin derivative with 2-aminothiophenol and 1,2,3-triazole side chain, preparation and application
  • Pleuromutilin derivative with 2-aminothiophenol and 1,2,3-triazole side chain, preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Preparation of intermediate Ⅰ: Dissolve 5.4g (14.27mmol) of pleuromutilin in 30ml of pyridine, cool it in ice to about 0°C, add 2.99g (15.70mmol) of p-toluenesulfonyl chloride, keep it warm at 30°C for 2 hours, then add 40ml of ice Quench the reaction with water; pour the reaction solution into a separatory funnel, first add 40ml of chloroform to separate layers, remove the water phase, then wash the organic phase twice with 80ml of sulfuric acid solution with a concentration of 2mol / L, and then wash the organic phase with 30ml of saturated sodium bicarbonate solution Wash the organic phase twice, and finally wash the organic phase twice with 80 ml of deionized water and dry with anhydrous sodium sulfate; dry the organic phase by rotary evaporation, add 15 ml of isopropanol to the residual solid and heat to dissolve, and a large amount of white powder is precipitated after cooling. Suction filtration under reduced pressure, the filtrate was washed with isopropanol, the p...

Embodiment 2

[0096] Example 2 22-O-[2-((4-((diethylamino)methyl)-1H-1,2,3-triazole)acetamido)phenyl]thioacetylmuulin ( Compound 1) Synthesis

[0097]Take 1g (13.67mmol) of diethylamine and dissolve it in 30ml of ethyl acetate, add 3.78g (27.34mmol) of potassium carbonate, then slowly add 1.63g (13.67mmol) of 3-bromopropyne into the reaction system, and keep warm at 20°C Stir the reaction for 3 hours, pour the reaction solution into a separatory funnel, add 40ml of chloroform for extraction, wash twice with aqueous sodium chloride (15% w / v) and dry with anhydrous sodium sulfate, take the organic phase; The intermediate V-1 with the following structure was obtained by rotary evaporation;

[0098]

[0099]

[0100] Take 1g (1.70mmol) of intermediate IV and 0.19g (1.70mmol) of intermediate V-1 and dissolve them in a mixture of 10ml tert-butanol and 10ml water, add 0.0033g (0.068mmol) of copper sulfate pentahydrate and sodium ascorbate 0.0013g (0.068mmol), keep warm at 20°C and stir for...

Embodiment 3

[0101] Example 3 22-O-[2-((4-((morpholinyl)methyl)-1H-1,2,3-triazole)acetamido)phenyl]thioacetylmuulin (compound 2) synthesis

[0102] Take 1.19g (13.67mmol) of morpholine and dissolve it in 30ml of dichloromethane, add 3.78g (27.34mmol) of potassium carbonate, then slowly add 1.63g (13.67mmol) of 3-bromopropyne into the reaction system dropwise, and keep warm at 25°C Stir the reaction for 3 hours, pour the reaction solution into a separatory funnel, add 40ml of chloroform for extraction, wash twice with aqueous sodium chloride (15% w / v) and dry with anhydrous sodium sulfate, take the organic phase; The intermediate V-2 with the following structure was obtained by rotary evaporation;

[0103]

[0104] Take 1g (1.70mmol) of intermediate IV and 0.21g (1.70mmol) of intermediate V-2 and dissolve them in a mixture of 10ml tert-butanol and 10ml water, add 0.0033g (0.068mmol) of copper sulfate pentahydrate and sodium ascorbate 0.0013g (0.068mmol), keep warm at 25°C and stir for ...

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Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with 2-aminothiophenol and a 1,2,3-triazole side chain, preparation and application. The pleuromutilin derivative with 2-aminothiophenol and the 1,2,3-triazole side chain is a compound of a formula 2 or a pharmaceutically acceptable salt of the compound, and a solvent compound, an enantiomer, a diastereomer and a tautomer of the compound of the formula 2 or the pharmaceutically acceptable salt of the compound or a mixture of the compound of the formula 2 or the pharmaceutically acceptable salt of the compound in any ratio, and includes a racemic mixture, and the compound has good inhibition to methicillin-resistant staphylococcus aureus activity, and is especially suitable forbeing used as a novel antibacterial drug for prevention and treatment of infectious diseases caused by human or animals or methicillin-resistant staphylococcus aureus or multi-drug resistant bacteria.(Please see the specification for the formula).

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a pleuromutilin derivative with 2-aminobenzenethiol and 1,2,3-triazole side chains, as well as its preparation and application. Background technique [0002] Pleuromutilin (Formula 1) was first isolated from the cultures of two basidiomycetes Pleurotus mutilus and P. passeckerianus by Kavanagh et al. in 1951. Its structure was determined by Birch et al. in 1966, and it was confirmed by X-ray crystallography that it is composed of a very rigid 5-6-8 tricyclic carbon skeleton with eight stereocenters and a glycolic acid chain of C(14). composed of compounds. Pleuromutilin is a tricyclic diterpene compound with a parallel (5-6-8) tricyclic ring. This type of compound interacts with the ribosome 50S subunit to inhibit bacterial protein synthesis, thereby inhibiting the growth of a variety of Gram-positive bacteria and mycoplasma antibiotics, basically does not affect ...

Claims

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Application Information

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IPC IPC(8): C07D249/04A61K31/4192A61K31/5377A61P31/04
CPCC07D249/04A61P31/04Y02A50/30
Inventor 靳珍张哲汤有志张光雨
Owner SOUTH CHINA AGRI UNIV
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