The invention relates to synthesis of tulathromycin, in particular to a reaction of (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-2-ethyl-3, 4, 10-trihydroxy-13-[[3S, 4S, 6R, 8R]-8-methoxy-4, 8-dimethyl-1, 5-dioxaspiro [2, 5] oct-6-yl] oxy) 3, 5, 8, 10, 12, 14-hexamethyl-11-[[3, 4, 6-trideoxy-3-(dimethylamino)-beta-D-xylopyranosyl] oxy]-1-oxa-6-azacyclopentadecane-15-one monohydrate with n-propylamine in the presence of a solvent and ytterbium trifluoromethanesulfonate, so as to realize the synthesis of tulathromycin.