Pleuromutilin compound and preparation method and application thereof

A technology of pleuromutilin and compounds, which is applied in the field of drug synthesis, can solve the problems of few candidate drugs or veterinary drugs, short half-life, poor water solubility, etc., achieve great economic and social benefits, and have little corrosion of equipment and strong The effect of antibacterial activity

Active Publication Date: 2018-12-04
SOUTH CHINA AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because pleuromutilin derivatives generally have poor water solubility, resulting in difficulty in absorption, short half-life, and low utilization rate, it is difficult to put them into use in clinical and veterinary production
So far, more than 1,000 derivatives have been obtained by modifying the structure of the pleuromutilin core, but there are still few effective drugs that can become candidate drugs or veterinary drugs

Method used

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  • Pleuromutilin compound and preparation method and application thereof
  • Pleuromutilin compound and preparation method and application thereof
  • Pleuromutilin compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 Preparation of p-tosylated pleuromutilin

[0066] (1) Dissolve pleuromutilin (10g, 26.46mmol) in 20mL ethyl acetate to obtain a pleuromutilin solution, then add p-toluenesulfonyl chloride (5.5g, 28.94mmol) to obtain a mixed solution; , add dropwise a sodium hydroxide solution with a concentration of 20 mol / L to the mixed solution until the pH of the system is 12.5, then remove the ice bath, react for 3 hours at 25°C, and the reaction is complete;

[0067] (2) Pour the reaction solution into a separatory funnel, first add 50 mL of chloroform for layering, remove the water phase, and finally wash the organic phase with 100 mL of water twice and dry with anhydrous sodium sulfate;

[0068] (3) Dry the organic phase by rotary evaporation, add 10mL isopropanol to the residual solid and heat to dissolve. After cooling, a large amount of white powder is precipitated, filtered under reduced pressure, and the filtrate is washed with isopropanol, and evaporated to drynes...

Embodiment 2

[0069] The preparation of embodiment 2 intermediate (I)

[0070] (1) Under nitrogen protection, add p-tosylated pleuromutilin (1g, 1.88mmol) and ethyl acetate (18.3mL, 188mmol) prepared in Example 1 into a three-necked flask equipped with a thermometer and a stirrer ), dissolved completely at room temperature;

[0071] (2) Add diaminobenzenethiol (0.31g, 2.44mmol) to 10mL of 10wt% sodium hydroxide solution cooled to 0°C to obtain a mixed solution of alkali solution and diaminobenzenethiol; then add the mixed solution dropwise To the reaction flask in step (1), react at 26°C for 3h; finally add TEBAC (0.09g, 0.376mmol), and heat at reflux at 75°C for 3h;

[0072] (3) After the reaction, extract the oil phase with dichloromethane, wash the organic phase with chloroform, saturated brine, and water successively, dry the ethyl acetate with anhydrous sodium sulfate, and obtain the crude product of intermediate (I);

[0073] (4) After dissolving the crude product of the above-menti...

Embodiment 3

[0074] The preparation of embodiment 3 pleuromutilin compounds

[0075] (1) Add o-toluic acid (0.34g, 2.47mmol) and dichloromethane (12.0mL, 188mmol) into a three-neck flask equipped with a thermometer and a stirrer, and dissolve completely at room temperature;

[0076] (2) Take 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.47g, 2.47mmol), 1-hydroxybenzotriazole (0.33g, 2.47mmol), Triethylamine (0.86mL, 6.19mmol) was added to the reaction flask, and reacted at 25°C for 5h; the intermediate (I) (1g, 2.06mmol) prepared in Example 2 was added to the reaction flask, and reacted at 25°C for 5h;

[0077] (3) After the reaction, the oil phase was separated with dichloromethane, washed with saturated brine and water, dried with phosphorus pentoxide, and then evaporated to dryness to obtain the crude product of pleuromutilin compounds;

[0078] (4) Dissolve the crude product of the above-mentioned pleuromutilin compound in methanol, add silica gel powder (200-300 mesh...

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Abstract

The invention belongs to the technical field of drug synthesis, and concretely relates to a pleuromutilin compound and a preparation method and an application thereof. The pleuromutilin compound has astructure shown in formula I, and is prepared by reacting p-toluenesulfonyl chloride and pleuromutilin to obtain p-toluene sulfonylated pleuromutilin; ethyl acetate dissolves p-toluene sulfonylated pleuromutilin; a cooled alkaline solution and diaminobenzenethiol are mixed; the toluene sulfonylated pleuromutilin is reacted with a mixed solution of an alkaline solution and diaminobenzenethiol; then benzyltriethylammonium chloride is added to obtain an intermediate (I); and the o-methylbenzoic acid or o-methylbenzoyl chloride is reacted with a condensing agent, a catalyst, an organic base and an intermediate (I) to obtain the pleuromutilin compound. The compound has the advantages that the raw material is cheap, the reaction liquid has little corrosion to the equipment, the production costis low, the yield is high, the purity is high, and the economic benefit and the social benefit are large, and the compound accords with the requirements of green ecology and sustainable development.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a pleuromutilin compound and its preparation method and application. Background technique [0002] Pleuromutilin is a diterpenoid with antibacterial activity produced by higher fungi. It has strong antibacterial activity against Gram-positive bacteria and mycoplasma, and its antibacterial mechanism is to bind to the site of the bacterial ribosomal 50s subunit, inhibit the transfer of peptide groups, and block the synthesis of the ribosomal 50s subunit. Pleuromutilin compounds have a core structure different from common clinical antibacterial drugs, and cross-resistance with other structural antibacterial drugs is not easy to occur. Tiamulin and warnimulin are such compounds as animal-specific antibacterial drugs Typical examples of successful development. Pleuromutilin drugs have a unique structure and antibacterial mechanism, so that they can produce drug resistance r...

Claims

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Application Information

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IPC IPC(8): C07C323/52C07C309/73C07C303/28C07C319/14C07C319/20A61P31/04
CPCA61P31/04C07C303/28C07C319/14C07C319/20C07C323/52C07C2603/82C07C309/73
Inventor 汤有志高鸿刘雅红张昭圣
Owner SOUTH CHINA AGRI UNIV
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