Hideo Yoshiwara

SYNTHESIS OF 5,6,7-TRINOR-4,8-INTER-M-PHENYLENE PGI2 AND BERAPROST

Abstract We have disclosed a new class of stable PGI 2 analogue, 5,6,7-trinor-4,8-inter- m -phenylene PGI 2 which has a phenyl ether moiety instead of enol-ether skeleton in PGI 2 . The m -phenylene PGI 2 and its derivative (Beraprost) were synthesized via dihydrocyclopenta[ b ]benzofuran derivatives as key intermediates by ortho -selective metal-halogen exchange reaction with Grignard reagents and subsequent copper-catalyzed cyclization. The ω-side chains were introduced by stereoselective epoxide formation or Prins reaction.

Preparative resolution of a key intermediate for the synthesis of optically active m-phenylene PGI2 derivatives

Abstract A key intermediate for the synthesis of optically active m -phenylene PGI 2 derivatives was efficiently resolved on a preparative scale by diastereomeric salt formation method using (+)- cis - N -benzyl-2-(hydroxymethyl)cyclohexylamine ((+)- cis -amine) as a resolving agent.

Preparative resolution of 2-methyl-4-hexynic acid for the synthesis of optically active m-phenylene PGI2 derivatives and determination of their absolute configuration

Abstract Racemic 2-methyl-4-hexynic acid, which is a starting material for the ω-side chain of the PGI2 derivatives, Beraprost and Iloprost, was efficiently resolved on a preparative scale by diastereomeric salt formation using quinine and cinchonidine as resolving agents. Their absolute configuration was determined by X-ray analyses of Beraprost derivatives.