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Challenging Macrolide Chemistry
Challenge
- Reactivity and selective protection/deprotection of five OH groups
- Sensitivity of macrolides towards basic and acidic conditions (epimerisation on C-2, lactone opening, sugar cleavage)
- No chromophore – difficult to monitor reaction progress (LC-MS and TLC with H2SO4)
- Complex purification of final products (precipitation, acid/base extraction, solid-phase extraction)
Introducing substituents at position 2’ of azithromycin
- Without protection: mixture of products (reaction proceeded on 2’-OH, 4’’-OH and 11-OH)
- With protection:
Challenge at step 3
- hydrolysis in MeOH at RT – two products (11,12-orthoamide and 11,12-orthoester)
- 45°C – only 11,12-orthoester (used for scale-up)
Challenge at step 5
- acetylation of 11-OH due to protecting group cleavage
- acetylation of 1° amine – avoided with neutralization
Summary
- An inventive protecting group strategy allowed regioselective alkylation at position 2′-OH
- 100 g scale
- Overall yield 5 % / 7 steps
- No column chromatography
- Low cost: 1g < $10
References
- Pešić D, et al., J Med Chem 2012, 55, 3216
- Starčević K, et al., Eur J Med Chem 2012, 49, 365
- Alihodžić S, et al., WO2010086351
- Alihodžić S, et al., WO2009016142