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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