Erythromycylamin

Nachstehend als ein Beispiel aus der Naturstoff-Chemie die zweite Stufe (Reduktion) der Umwandlung von Erythromycin-B in Erythromycylamin B iiber das Oxim. 

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. 

A n understanding of the acid-catalyzed de-compositionof erythromycin has led to a variety of semisynthetic derivatives with improved oral bioavailability (142). Reductive amination of the 9-keto function gives erythromycylamine. 

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... 

Comparative In Vivo Evaluation of 9-A-Substituted Erythromycylamine Derivatives... 

Timms, G. H., and Wildsmith, E. (1971). The reduction of oximes with tervalent titanium, a mild deoxymation procedure, and the partial synthesis of erythromycylamine. Tetrahedron Lett. 195-198. 

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

Cockerill, A. F., Ellis, M. F., Rackham, D. M., and Wildsmith, E. (1973). Substituent effects on the pKa values and rates of hydrolysis of arylmethylene-erythromycylamines. J. Chem. Soc. Perkin Trans II173-179. 

Maier, R., Woitun, E., Wetzel, B., and Lechner, U. (1988). Synthesis, structure, and biological activity of tetrahydro-l,3-oxazines derived from 9(S)-erythromycylamine and substituted acetaldehydes. Presented at 28th Intersci. Conf. Antimicrob. Agents Chemother (Oct. 23-26, Los Angeles). Abstr. No. 917. 

Lazarevski, T., Radobolja, G., and Djoklc, S. (1978). Erythromycin VI Kinetics of acid-catalyzed hydrolysis of erythromycin oxime and erythromycylamine. J. Pham. Sci. 67, 1031-1033. 

Yes. The production of the active metabolite erythromycylamine is partly responsible for the long half-life of the drug. 

Montenez JP, Van Bambeke F, Piret J, Brasseur R, Tulkens PM, Mingeot-Leclercq MP (1999) Interactions of macrolide antibiotics (erythromycin A, roxithromycin, erythromycylamine [Dmthromycin] and azithromycin) with phospholipids computer-aided conformation analysis and studies on acellular and cell culture models. Toxicol Appl Pharmacol 156 129-140 Morgan MY, Reshef R, Shah RR, Oates NS, Smith RL, Sherlock S (1984) Impaired oxidation of debrisoquine in patients with perhexiline liver injury. Gut 10 1057-1064 Morris AAM (1999) Mitochondrial respiratory chain disorders and the liver. Liver 19 357-368 Morris AAM, Taanman JW, Blake J, Cooper JM, Lake BD, Malone M, Love S, Clayton PT, Leonard JV, Schapira AHV (1998) Liver failure associated with mitochondrial DNA depletion. J Hepatol 28 556—563... 

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... 

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