合成路线1

Treatment of 2,6-dichloropyridine (I) with butyllithium in THF followed by quenching with CO2 affords 2,6-dichloronicotinic acid (II) . After chlorination with boiling SOCl2, the resulting acid chloride (IIIa) is condensed with diethyl malonate by means of magnesium ethoxide in Et2O to give the nicotinoyl acetate (IV) . Alternatively, activation of 2,6-dichloronicotinic acid (II) with CDI provides imidazolide (IIIb) which, without isolation, is condensed with the potassium salt of diethyl malonate in the presence of MgCl2 and Et3N to yield the keto ester (IV) . Treatment of compound (IV) with triethylorthoformate and acetic anhydride followed by reaction with 2-aminothiazole (V) gives the enamino ester (VI), which is cyclized to the 1,8-naphthyridine derivative (VII) upon heating with K2CO3 in dioxane . Condensation of chloronaphthyridine (VII) with the chiral pyrrolidine (VIII) by means of triethylamine in acetonitrile yields the protected voreloxin (IX), which is finally hydrolyzed with hot aqueous HCl . In a related method, chloronaphthyridine (VII) is coupled with the unprotected pyrrolidine (X) to afford voreloxin ethyl ester (XI), which is finally hydrolyzed with NaOH in H2O/EtOH .