The intermediate aldehyde (VII) has been obtained as follows: The cyclization of 2-fluoro-4-hydrazinobenzonitrile (I) with malonaldehyde (II) by means of HCl in refluxing ethanol gives 2-fluoro-4-(1-pyrazolyl)benzonitrile (III), which is reduced by means of diisobutylaluminum hydride in toluene to yield the benzaldehyde (IV). The condensation of (IV) with (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (V) by means of TDA-1 and K2CO3 in refluxing dichloromethane to afford the 3-[2-fluoro-4-(1-pyrazolyl)phenyl]-2-propenal ethylene ketal (VI), which is finally hydrolyzed with HCl in THF to provide the target intermediate aldehyde (VII).
The reaction of erythromycin A (VIII) with Ac2O, TEA and DMAP in dichloromethane gives the triacetate (IX), which is treated with NaHMDS in THF to yield the unsaturated erythromycin derivative (X). The treatment of (X) with trichloroacetyl isocyanate (XI), followed by reaction with TEA and t-BuOK affords the cyclic carbamate (XII). The acylation of the 2'-OH of (XII) with Ac2O and TEA, followed by cleavage of its cladinose sugar by means of HCl in ethanol/water provides compound (XIII), which is oxidized and deacetylated to give the ketolide derivative (XIV). Finally, this compound is reductocondensed with the intermediate aldehyde (VII) by means of Tes-H and TFA in acetonitrile to yield the target substituted ketolide.