新規な安定PGI₂誘導体m-フェニレンPGI₂の合成研究

ベラプロストナトリウムの製造法開発

抄録

Just after the discovery of PGI₂, we started to find chemically and metabolically stable PGI₂ derivatives with longer duration of action. Extensive studies led us to a new class of stable PGI₂ analogue, 5, 6, 7-trinor-4, 8-inter-m-phenylenePGI₂ that has a phenol moiety instead of enol-ether linkage in PGI₂. In order to accomplish synthesis of the m-phenylenePGI₂, novel synthetic methods were developed, for instance, ortho-selective metal-halogen exchange reaction of bromoanisoles by means of Grignard reagent, copper-catalyzed S_N2' cyclization to prepare dihydrocyclopenta [b] benzofuran, and regioselective and stereo-selective elongation of ω-side chain by Prins reaction. Further efforts were devoted to synthesize derivatives of m-phenylenePGI₂ with enhanced pharmacological activity and less adverse reaction. Finally, we attained to Beraprost sodium which is the first launched drug as an orally active PGI₂. This paper will focus on the study of total syntheses of m-phenylenePGI₂.