CARBOXYLATION OF KINETICALLY INERT PLATINUM(IV) HYDROXY COMPLEXES - AN ENTREE INTO ORALLY-ACTIVE PLATINUM(IV) ANTITUMOR AGENTS

Carboxylation of hydroxide coordinated to Pt(IV) by anhydrides, pyroca rbonates, and isocyanates to form the corresponding Pt(IV) carboxylate s, carbonates, and carbamates is described. For example, the acylation with acetic anhydride of minedichloro(cyclohexanamine)dihydroxyplatin um(IV) leads to formation of tato-O)amminedichloro(cyclohexanamine)pla tinum(IV) (JM-216) in 60% yield. This compound is currently in worldwi de clinical trials as an orally active antitumor agent. Pt(IV) dicarbo nates and dicarbamates are prepared similarly by reaction of a Pt(IV) hydroxide with a pyrocarbonate or isocyanate. The carboxylation reacti on can be used to prepare molecules containing ligands with pendant fu nctional groups that would be difficult to introduce by substitution r eactions. Thus ohexanamine)bis((methylthio)acetato-O)platinum(IV) was prepared, which was oxidized to the corresponding sulfoxide namine)bis ((methylsulfinyl)acetato-O)platinum(IV). Finally, unsymmetrical carbox ylate complexes may be obtained by reaction of a binary mixture of two electrophiles with a Pt(IV) hydroxide followed by chromatographic sep aration of the carboxylation products. A simplified synthesis of the K [(PtCl3NH3)-Cl-II] in 55% yield from cisplatin is also reported. This improves the availability of molecules of the general formula cis-Pt-I I-Cl(2)AA' (A, A' = ammine, amine) which are critical intermediates in the multistep synthesis of the Pt(IV) carboxylates having antitumor a ctivity.