Valnemulin prodrug as well as preparation method and detection method thereof

A technology of warnemulin and prodrug, which is applied in the field of warnemulin prodrug and its preparation, can solve the problems of no structure, large molecular weight, and difficult analysis of nuclear magnetic spectrum, etc., and achieve good stability and drug loading capacity precise effect

Inactive Publication Date: 2015-09-23
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The molecular weight of PEG is 2,000 to 75,000, which is a relatively large molecular weight and is a complex mixture. The molecular weight of the macromolecular warnemulin is 564.8. The nuclear magnetic spectrum obtained from the prodrug of warnemulin may be difficult to analyze, and it may be difficult to see or even find the original Therefore, it is of great significance to develop a method that can detect the prodrug of warnemulin

Method used

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  • Valnemulin prodrug as well as preparation method and detection method thereof
  • Valnemulin prodrug as well as preparation method and detection method thereof
  • Valnemulin prodrug as well as preparation method and detection method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment １

[0059] Embodiment 1 The preparation method of ethylene glycol monomethyl ether-Varnemulin

[0060] The chemical reaction formula is as follows:

[0061] (1) Synthesis of ethylene glycol monomethyl ether-succinic acid:

[0062]

[0063] In a 50 mL three-necked flask, add ethylene glycol monomethyl ether (6.08 g, 0.08 mol), stir magnetically, add succinic anhydride (6.4 g, 0.064 mol), add 30 mL of toluene, stir fully to dissolve it, and heat Reaction at 80 °C for 4 h, monitored by TLC (developing solvent: PE:EA=5:1). After the reaction was completed, toluene was removed by distillation under pressure, and saturated NaHCO was added 3 Solution (50 mL) was adjusted to pH=8, ethyl acetate (20 mL×3) was used to extract impurities, the aqueous phase was taken, adjusted to pH 2~3 with 1 mol / L hydrochloric acid, dichloromethane (20 mL×4) was extracted, and the organic phase Wash with saturated brine until neutral, reverse extraction with water, dry the organic phase by adding anhy...

Embodiment 2

[0074] The preparation method of embodiment 2 warnemulin prodrug

[0075] (1) Synthesis of PEG derivatives with carboxyl groups at the end:

[0076]

[0077] Add PEG (molecular weight: 2000) (20 g, 10 mmol), toluene (80 mL), and dry pyridine (2 mL) into a 250 mL three-neck flask, stir magnetically and heat to 60°C to dissolve, and succinic anhydride (2.5 g, 25 mmol) was dissolved in toluene (20mL) at 60°C, and the dissolved succinic anhydride was slowly dropped into the dissolved PEG or mPEG, and reacted at 60°C for 1h, and the temperature was raised to 80°C for 36h . After the reaction was completed, the temperature was naturally lowered, the solvent was removed by rotary evaporation, and saturated NaHCO was added to the residue. 3 The solution (60 mL) was stirred for 30 min, and a white milky substance was produced during the addition, filtered through a Buchner funnel, and the filtrate was extracted with ethyl acetate (20 mL×5), the water phase was taken, cooled to 0-5...

Embodiment 3-7

[0126] Embodiment 3-7 Warnemulin prodrug and preparation method thereof

[0127] Embodiments 3-7 are respectively a warnemulin prodrug and its preparation method, which are similar to those in Example 2, except that the PEG or mPEG modifiers are different and the technical parameters involved are different, see below for details surface:

[0128]

[0129]

[0130]

[0131]

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Abstract

The invention discloses a valnemulin prodrug as well as a preparation method and a detection method thereof. The provided valnemulin prodrug has good stability and overcomes the weakness that the half attenuation period of the valnemulin prodrug is only 1.3 to 2.7 hours, the prepared prodrug has a controlled-release action, and the in-vitro release experiment shows that the valnemulin prodrug can reach the maximum value in 8 hours. Since valnemulin molecules have a plurality of active reaction sites, a method for determining a reaction site for connecting the carrier and valnemulin is a method for adopting a single-molecular carrier to react with valnemulin, the obtained single-molecular prodrug is determined as the reaction site of the valnemulin by virtue of nuclear magnetic detection, and the prodrug reaction site obtained in the method is two amino acids of the valnemulin; the valnemulin prodrug with relatively high drug loading capacity can be prepared; the drug loading capacity of the prepared PEG-valnemulin prodrug is determined by adopting a UV, HPLC-UV and HPLC-ELSD combination method, so that the measured drug loading capacity is more accurate. The method is suitable for preparing and detecting the valnemulin prodrug.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a prodrug, a preparation method and a detection method thereof, in particular to a warnemulin prodrug, a preparation method and a detection method thereof. Background technique [0002] Warnemulin belongs to the pleuromutilin class of veterinary antibiotics. It mainly acts on the 50S ribosomal subunit of bacteria. By inhibiting the activity of peptidyl transferase, it hinders the synthesis of bacterial proteins, thereby realizing the antibacterial effect. Warnimulin has a wide antibacterial spectrum and is effective against G+, G- and mycoplasma bacteria. Actinobacillus pneumoniae and Lawsonia intracellulare have strong inhibitory effect, especially highly sensitive to mycoplasma and spirochete. The water solubility and stability of warnemulin itself are very poor, and it is usually necessary to prepare it into warnemulin hydrochloride to improve its water solubility and stability. Vernim...

Claims

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Application Information

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IPC IPC(8): C08G65/00C08G65/48A61K31/22A61K47/48
Inventor 张越徐世霞杨吉霞宋永兴赵树春
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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