Erythromycylamine Dirithromycin

Erythromycylamine (20 g, 1 eq) was added over a 20 minute period and stirring continued for 12-16 hours at 23°C. The reaction mixture was cooled to 0°C for 2 hours and then filtered to recover dirithromycin crystals. The crystals were washed with cold acetonitrile and dryed in vacuo at 40°C. The... 

Liu, Y.Q. et al. Quantitative determination of erythromycylamine in human plasma by liquid chromatography-mass spectrometry and its apphcation in a bioequivalence study of dirithromycin. J. Chromatogr. A. 2008, 864, 1-8. 

Dirithromycin 500 mg q. 24 hr No renai adjustment required Nonenzymatically hydrolyzed to actiye compound erythromycylamine. NC NC Dose for GFR 10-50 ml/min... 

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). 

Erythromycylamine (9a), the key intermediate for dirithromycin (20) synthesis, could be prepared from any of the EM 9-oxime (11), EM 9-hydrazone... 

The product of another approach to replacement of the ketone in erythromycin is dirithromycin (14), a 9-A, ll-0-oxazine derivative of 9(S)-amino-9-deoxoerythromycin (9(5)-erythromycylamine, 15) [101, 102]. R stereochemistry of the substituent at C-2 of the oxazine was established by X-ray crystallography [101]. Condensation of erythromycylamine with 2-methoxyethoxyacetaldehyde initially gives the 2(5)-oxazine, which was isolated using diethyl ether as solvent, but it rapidly epimerizes to dirithromycin [103, 104]. A related compound with 5 stereochemistry of the oxazine substituent has also been crystallized [105]. Both epimers readily... 

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]. 

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