Novel Macrolide Antibiotics - Fidelta.eu

» 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

Copyright © 2019 All Rights Reserved - Fidelta Ltd.