Toward the Synthesis of Verteporfin from Hemin and Protoporphyrin IX

This report describes two approaches toward verteporfin (benzoporphyrin derivative monoacid), a photosensitizer used in photodynamic therapy. One starts from hemin and the other from commercial protoporphyrin IX (PpIX). The hemin route first converts hemin into PpIX dimethyl ester, by reductive removal of iron and concomitant acid-catalyzed esterification. The benzoporphyrin skeleton of verteporfin is then built from PpIX dimethyl ester by a Diels-Alder cycloaddition with dimethyl acetylenedicarboxylate (DMAD). The vinyl group and the neighboring pyrrole double bond of ring A or ring B act as the diene, and the activated alkyne adds to them to form a new six-membered ring carrying two methyl ester groups. Throughout the sequence, reaction progress was monitored by UV-visible spectroscopy, thin-layer chromatography, HPLC, and 1H NMR spectroscopy. The Diels–Alder step was studied under three activation conditions: reflux in 1,2-dichloroethane (bp 83.5 °C) and in 2-methyltetrahydrofuran (bp 80 °C), both in an oil bath set to 85 °C, and microwave irradiation at 100-140 °C. The HPLC, NMR and UV-visible data are consistent with partial conversion to benzoporphyrin products, but the products were not isolated and their structures were not confirmed at this stage. The work provides a critical assessment of the reaction parameters governing the key cycloaddition and identifies the main limitations encountered in each step, with a view to informing future optimization of the process.