HMR-3787

合成路线:The title compound was prepared by stereoselective fluorination of the known ketolide (I) at position 2 by means of N-fluorosulfonimide and NaH.

合成路线:Direct fluorination of telithromycin (I) at position 2 by means of N-fluorosulfonimide and NaH afforded the title compound in low yield,along with a geater amount of the N-demethylated analogue.In a modified procedure,protection of the 2' hydroxyl group of (I) as the trimethylsilyl ether (II),followed by fluorination with N-fluorosulfonimide in the presence of potassium tert-butoxide provided fluoroketolide (III).Subsequent desilylation of (III) by means of tetrabutylammonium fluoride then furnished the title compound in high yield.

合成路线:In an alternative synthesis,compound (IV) was protected as the silyl ether (V) and then fluorinated by means of N-fluorosulfonimide and potassium tert-butoxide.The resulting fluorinated derivative (VI) was desilylated by means of tetrabutylammonium fluoride to yield (VII),which was further protected as the 2'-acetate ester (VIII).Treatment of (VIII) with 1,1'-carbonyl diimidazole produced the acyl imidazole (IX).Subsequent condensation of (IX) with amine (X) gave rise to the corresponding 11,12-cyclic carbamate,which was finally deacetylated upon treatment with MeOH.

合成路线:Treatment of macrolide (I) with O-methylhydroxylamine hydrochloride produced the 9-oxime (II) with concomitant deacetylation.Reductive condensation of (II) with pyridylimidazolylpropionaldehyde (III) in the presence of NaBH3CN gave adduct (IV),which was reprotected as the acetate ester (V).Fluorination of (V) at position 2 to afford fluorolactone (VI) was achieved by treatment of the corresponding potassium enolate with 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor(TM)).The title compound was finally obtained by deacetylation of (VI) in hot MeOH.
参考文献标题:Novel fluoroketolides: Synthesis and antibacterial activity
文献作者:Bonnefoy,A.; Denis,A.
参考来源:Drugs Fut 2001,26(10),975