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Novel Macrolide Antibiotics

Objective

  • Synthesis of new macrolides active towards resistant bacterial strains
  • Design and implement synthesis of new macrolide analogues
  • Preparation of macrolide derivative for in vivo studies (0.1 g scale, purity > 95.0 %, 50 g scale, purity > 98.5 %)

Challenge

  • Develop suitable synthetic route for industrial production in given timeframe (3 months)

Target molecule with three points of diversity

Synthesis of quinolone intermediate

Small scale synthesis

  • 0.1 g scale
  • 50% of desired product in the  reaction mixture
  • Not suitable for scale up
  • Desired compound: 6 steps  & 5%  overall yield   

Optimized procedure for chloroquinolone synthesis-summary

  • Scale up synthesis:
  • 50 g scale
  • Suitable for further scale up
  • overall yield ~ 19 % / 10 steps                                                             

 

New method for selective diethyleneglycol oxidation was developed

Quinolone intermediate - optimized synthetic route

Synthesis of macrolide derivatives

Large scale vs small scale synthesis

  • Low b.p. solvents avoided, i-PrOH used instead of DCM
  • Used isolation techniques more suitable for industrial production
  • Crystallization instead of extraction
  • Acid-base extraction instead of column chromatography
  • Improved overall yield; 61% large scale vs 32% small scale for 3 steps

Scale up of Azithromycin analogue

In vitro antibacterial activity

Summary

  • A new macrolide antibiotic was designed and synthesised
  • Synthesis of each step optimised for large scale
  • Innovative chemistry of diethylenglycol oxidation

Reference

  • A. Fajdetić, et al., Synthesis, activity and pharmacokinetics of novel antibacterial 15-membered ring macrolones
    Eur J Med Chem 2011, 46, 3388-3397
  • S. Alihodžić, et al., Ester linked macrolides useful for the treatment of microbial infections
    WO2005108412

  • A. Vinter, et al., An expeditious method for the preparation of 2-hydroxy-1,4-dioxane and its use in reductive alkylation of amines
    Synthesis 2010, 2, 255-258
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