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Rhubarb acid ester derivative and preparation method and application thereof

A technology of rhein esters and derivatives, applied in chemical instruments and methods, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve the problems of limiting the application of rhein, low bioavailability, and not particularly ideal solubility, etc. question

Active Publication Date: 2018-12-21
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, since rhein has an anthraquinone tricyclic aromatic structure, its solubility is not particularly ideal, it is insoluble in water, ethanol and most organic solvents, and its bioavailability in vivo is low, which greatly limits the use of rhein. Clinical application

Method used

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  • Rhubarb acid ester derivative and preparation method and application thereof
  • Rhubarb acid ester derivative and preparation method and application thereof
  • Rhubarb acid ester derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of O',O-Dimethyl-α-rheinyl-α-phenyl-phosphonic acid methyl ester (Ⅱa)

[0026] 2.0mmol rhein, 2.2mmol intermediate I (dimethyl α-hydroxybenzylphosphonate), and 1.0mmol [Bmim] BF 4 Add the ionic liquid into the three-necked flask, then add 2.0mmol DCC and 1.6mmol DMAP to the three-necked flask at 0-5°C, and finally add 40mL of anhydrous dichloromethane into the reaction flask, put it into an ultrasonic synthesizer, and set it at a power of 100W , naturally warming up to 20° C., maintaining the temperature and stirring for 20 minutes. After completion, filter and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography, and finally the target product is obtained as a light yellow solid (IIa), with a yield of 84.3%. compound 1 H NMR and 13 C NMR: 1 H-NMR (400MHz, CDCl 3 )δ:12.08(s,1H,OH),11.99(s,1H,OH),7.80-7.85(m,2H,ArH),7.63(s,1H,ArH),7.22-7.40(m,7H,ArH ),6.55(s,1H,PCH),3.32-3.40(m,6H,2OCH 3 ...

Embodiment 2

[0028] Preparation of O',O-diethyl-α-rheinyl-α-o-fluorophenyl-phosphonic acid methyl ester (Ⅱb)

[0029] 2.0mmol of rhein, 2.2mmol of intermediate Ⅰ (diethyl α-hydroxy-o-fluorobenzylphosphonate), and 1.0mmol of [Bmim] BF 4 Add the ionic liquid into the three-necked flask, then add 2.0mmol DCC and 1.6mmol DMAP to the three-necked flask at 0-5°C, and finally add 60mL of anhydrous dichloromethane into the reaction flask, put it into an ultrasonic synthesizer, and operate it at a power of 100W , naturally warming up to 25° C., maintaining the temperature and stirring for 15 minutes. After completion, the crude product was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography, and finally the target product was obtained as a light yellow solid (IIa), with a yield of 82.6%. compound 1 H NMR and 13 C NMR: 1 H-NMR (400MHz, CDCl 3 )δ:12.08(s,1H,OH),11.98(s,1H,OH),7.84-7.90(m,2H,ArH),7.69-7.73(s,1H,ArH),...

Embodiment 3

[0031] Preparation of O',O-diethyl-α-rheinyl-α-(2-furyl)-phosphonic acid methyl ester (Ⅱc)

[0032] 2.0mmol rhein, 2.2mmol intermediate Ⅰ [α-hydroxy-(2-furylmethyl) phosphonic acid diethyl ester], and 1.0mmol [Pmim] [HSO 4 ] Add the ionic liquid into the three-necked flask, then add 2.0mmol DCC and 1.6mmol DMAP to the three-necked flask at 0-5°C, and finally add 100mL of anhydrous dichloromethane into the reaction flask, put it into an ultrasonic synthesizer, and 80W, naturally raised the temperature to 20°C, maintained the temperature and stirred for 30min to react. After completion, filtered and concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography, and finally the target product was obtained as a light yellow solid (Ⅱa), with a yield of 85.0% . compound1 H NMR and 13 C NMR: 1 H-NMR (400MHz, CDCl 3 )δ:12.08(s,1H,OH),11.97(s,1H,OH),7.88-8.01(m,2H,ArH),7.12-7.35(m,4H,ArH),6.72-6.87(m,2H ,ArH),6.44(s,1H,P...

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Abstract

The invention discloses a rhubarb acid ester derivative in the field of antibiotic compounds. The chemical structural formula of rhubarb acid ester is as shown in the formula (II), the formula (II) isshown in the description, wherein R is a chain substituent group of 1-5 carbon atoms or a naphthenic base or an aromatic hydrocarbon group of 3-6 carbon atoms. An antibiotic activity test proves thatthe rhubarb acid ester derivative with the novel structure has the antibiotic activity on methicillin-resistant staphylococcus aureus (MRSA). A plurality of targets have the outstanding antibiotic effect on methicillin-resistant staphylococcus aureus (MRSA), are superior to the reference drug oxacillin and is close to the reference drug vancomycin, and the rhubarb acid ester derivative can be served as a candidate compound to resist methicillin-resistant staphylococcus aureus (MRSA) and be researched.

Description

technical field [0001] The invention belongs to the field of antibacterial compounds, and in particular relates to a rhein ester derivative and its preparation method and application. Background technique [0002] The discovery of antibiotics has brought unprecedented benefits to the treatment of infectious diseases. However, with the overuse or even abuse of antibiotics in clinical practice, antibiotic-resistant bacteria have also emerged and are increasing day by day. Among them, methicillin-resistant Staphylococcus aureus (MRSA), which was discovered in 1961, has the characteristics of high morbidity and mortality, and its clinical treatment is very difficult. At present, in clinical practice, the last line of defense in the treatment of MRSA infection is glycopeptide antibiotics represented by vancomycin. However, with the discovery and detection of vancomycin-resistant Staphylococcus aureus (VRSA), in the future, MRSA may face a point where there is no cure. Therefor...

Claims

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Application Information

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IPC IPC(8): C07F9/40A61K31/663A61P31/04
CPCA61P31/04C07F9/4059
Inventor 杨家强赵仕新安家丽邓玲雷延燕
Owner ZUNYI MEDICAL UNIVERSITY
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