Chemical modification of erythromycins. IX. Selective methylation at the C-6 hydroxyl group of erythromycin A oxime derivatives and preparation of clarithromycin.

Although erythromycin A contains five hydroxyl groups, regioselective methylation at the C-6 hydroxyl group was achieved to the extent of 90% when a 9-O-substituted erythromycin A 9-oxime was employed as substrate. The methylation and its selectivity are dependent on an O-protecting group at the 9-oxime, solvent, base, and methylating reagent. In particular, the use of a polar aprotic solvent is indispensable for the methylation. Among the 9-oxime derivatives, 2'-O,3'-N-bis(benzyloxycarbonyl)-N-demethylerythromycin A 9-[O-(2-chlorobenzyl)oxime] was the most important intermediate for the synthesis of clarithromycin (6-O-methylerythromycin A).