Читать книгу Routes to Essential Medicines - Peter J. Harrington - Страница 24

Anti‐Infective Medicines/Antibacterials/Other Antibacterials

Anti‐Infective Medicines/Antibacterials/Antituberculosis Medicines

A single‐enantiomer molecule with multiple chiral carbons is often made by modification of a natural product which has most or all of the chiral carbons already in place.

Discussion. Amikacin is semisynthetic. Amikacin is formed by acylation of the amino group at C1 of kanamycin A. This selective acylation requires a protection–deprotection strategy since kanamycin A has four amino groups and the amino group at C1 is not the most reactive.

Three of the amino groups of amikacin are released in the final step by benzyl carbamate hydrogenolysis. The amide at C1 is formed by reaction of the amino group with an N‐hydroxysuccinimide ester. Amino groups at C3 and C6′ of kanamycin A are protected as benzyl carbamates (Cbz). Kanamycin A is produced by fermentation.

The N‐hydroxysuccinimide ester is formed from the carboxylic acid. The amino group of the 4‐amino‐2‐hydroxybutanoic acid is protected as the benzyl carbamate. (S)‐4‐Amino‐2‐hydroxybutanoic acid is formed from (S)‐2‐hydroxyglutaramic acid (Hofmann Rearrangement). The amide is formed from the lactone. (S)‐5‐Oxotetrahydrofuran‐2‐carboxylic acid lactone is formed by diazotization of L‐glutamic acid. L‐Glutamic acid is produced by fermentation.