Improvements in the synthesis and understanding of the iodo-bridged intermediate en route to the Pt(IV) prodrug satraplatin

• A new synthetic approach to preparing and using iodo-bridged platinum(II) dimers.
• New method is orders of magnitude faster and avoids common side products.
• Interpretation of the dimer cleavage mechanism that reconciles previous debate.
• Spectroscopic and crystallographic characterization of [Pt(NH2C6H11)I(μ-I)]2.

Mixed amine/ammine motifs are important features in newer generation platinum anticancer agents, including the Pt(IV) prodrug satraplatin. One synthetic route that can be used to access platinum molecules with such structures exploits the trans effect during NH3-mediated cleavage of iodo-bridged platinum(II) dimers of the form [Pt(Am)I(μ-I)]2, where Am is an amine. A clear picture of the nature of these dimers that is consistent with the reactivity they exhibit has remained elusive. Moreover, technical aspects of this chemistry have impeded its more widespread use. We present here an improved strategy that permits isolation and use of [Pt(Am)I(μ-I)]2, where Am is cyclohexylamine, within minutes as opposed to weeks, as previously reported. A detailed spectroscopic, crystallographic, and chromatographic investigation of this intermediate in the synthesis of satraplatin is also presented with a discussion of the ability of both cis and trans isomers of the dimer to produce exclusively cis-[Pt(NH2C6H11)(NH3)I2] upon treatment with NH3.

The chemistry of the iodo-bridged intermediate in the synthesis of satraplatin has been investigated.Figure optionsDownload as PowerPoint slide