Erythromycin hydrazone

Wildsmith, E. (1972). The reaction of erythromycin hydrazone with nitrous acid, a new route to erythromycylamine. Tetrahedron Lett. 29-30. 

Several structural modifications of the C-9 ketone of erythromycin have been explored oximes and hydrazones are less prone to intramolecular cydization, but they often have less antibiotic activity than erythromycin (140). Synthesis of more complex oxime derivatives resulted in the development of roxithromycin, the 9-[0-(2-methoxyethoxy)methyl]oxime (33) (141). Reduction of the oximes and hydrazones produced 9(S)-erythromycylamine (34) as the principal product, with minor amounts of the 9(R)-isomer (140) however, clinical studies showed that 9(5)-erythromycyclamine and its N-benzylidene derivative were poody absorbed in humans (142). Evaluation of more complex oxazine derivatives of erythromycylamine led to dirithromycin, the 2-(2-methoxyethoxy)ethylidene oxazine derivative (35) (143). A third route to modification of the ketone utilized a Beckmann rearrangement of the 9-oxime to expand the 14-membered ring to a 15-membered intermediate, which was subsequently reduced and AT-methylated to yield azithromycin (36) (144,145). The term azalide was proposed to denote these 15-membered azalactones (10,145). 

The structure of desosamine was elucidated independently in three laboratories. Clark examined the hydrolysis of erythromycin with 6 N hydrochloric acid. In addition to a tar soluble in organic solvents, a water-soluble, reducing base was isolated as a crystalline hydrochloride having the formula CsHitNOs-HCI. This product was found to consume 2 moles of periodate per mole with the formation of 1 mole of dimethylamine, 2 moles of formic acid, and 1 mole of aldol, but no formaldehyde. The aldol was isolated as the (2,4-dinitrophenyl)hydrazone of crotonaldehyde, the dehydration product of aldol. A C-methyl group was detected by the iodoform reaction. The dimethylamino group was readily eliminated under alkaline conditions, suggesting that it was present in a position /3 to the... 

The older oximes, hydrazones and imines of erythromycin are still employed as intermediates to 9-deoxo-9(S)-9-aminoerythromycin (erythromycylamine), formally the result of reductive amination of the ketone. Although it has excellent antibiotic properties, it is poorly absorbed when administered orally. In earlier efforts to overcome its poor oral bioavailability, some adducts of erythromycylamine with aldehydes and ketones were synthesized, but they were not developed for clinical use due to low blood levels after oral administration to man [30]. 9-iV-ll-O-Oxazine derivatives can be prepared by condensation of aliphatic aldehydes with erythromycylamine from a more recently prepared series of oxazines, the adduct from erythromycylamine and (2-methoxyethoxy)-acetaldehyde, named dirithromycin (see Fig. 4), was selected for clinical development on the basis of its high tissue levels [31]. 

---