The invention belongs to the technical field of chemistry, and particularly relates to a synthetic method of azithromycin impurity F. The combination method of the azithromycin impurity F-(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-nucleus-pyranohexyl pyrranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(N-methylformamido)-beta-D-pyranohexyl]oxy]-1-oxa-6-azacyclopentadecane-15 ketone in (formula I) comprises the main steps as follows: enabling azithromycin (compound II) to be subjected to 3'-N demethylation, performing formylation by using ethyl formate to generate a target product; purifying and then obtaining oxidized impurity with purity greater than 99.5%. The synthesized high-purity azithromycin impurity Fserves as impurity standard substance for finished product detection, is conducive to reinforcing location and nature determination of impurity, and improves quality control on azithromycin bulk drugs.