Radical hydroxymethylation of camptothecin (I) by means of MeOH in the presence of H2O2 and FeSO4 provided (II). Subsequent heating of alcohol (II) in acetic acid gave rise to 7-formylcamptothecine (III). Finally, condensation of aldehyde (III) with O-t-butylhydroxylamine afforded the corresponding oxime.
The title imine derivative was prepared by condensation of the known 7-formylcamptothecin (I) with aniline (II) in the presence of ytterbium triflate and molecular sieves in CH2Cl2.
Semisynthesis: Treatment of camptothecin (XI) with tert-butylhydroperoxide in the presence of FeSO4, conc. H2SO4 and acetic acid in water gives (S)-7-methylcamptothecin (XII). Mannich reaction of compound (XII) with isopropylamine hydrochloride in DMSO as a formaldehyde source gives CKD-602.