An eight synthesis of an orally active antihypertensive carba-prostacyclin analog

Article abstract of DOI:10.1016/S0040-4039(00)94119-4

A short synthesis of carbacyclin analog 1 (code no. EMD 46 335) starting from cyclopentadiene is described, with on overall yield of better than 5%. There is a need for a prostacyclin analog that is stable both chemically and metabolically. Chemical stability can be achieved by replacing to oxygen atom of the enolether function by a carbon atom (→ carbacyclin). Metabolical stability can - for instance - be enhanced by adding a substituent to the C₁₅ or C₁₆ carbon atom. To proceed on this line: since PGI₃ is more active than PGI₂, replacement of the C_16-20^-n-pentyl chain by a phenyl group should furthermore result in an enhancement of activity. Replacement of the C_13-14-vinyl moiety by a S-CH₂-link was thought to provide compounds more convenient to synthesize. We also were interested in designing a prodrug to the active part that does not only give rise to an enhanced shelf stability but also was to facilitate purification (i.e. 5 E,Z-separation) on the last step of its synthesis. On the other hand, it had to be labil enough to readily be activated in vivo and in vitro.