Practical Synthesis of Novel Cardioprotective Drug, CP-060S

Abstract

A practical synthesis of a novel cardioprotective drug, CP-060S, is described. Key intermediate (S)-7, a chiral carboxylic acid, was prepared from 3,5-di-tert-butyl-4-hydroxybenzaldehyde 2 by employing thiazolidinone cyclocondensation followed by selective crystallization from a diastereomeric salt mixture which was prepared by treating racemic 7 with (S)-(−)-N-benzyl-α-methylbenzylamine 11. Racemization of the (R)-7-rich mixture, obtained from the mother liquid, by treatment with NaOH solution and subsequent resolution gave a second crop of (S)-7. Resolving agent 11 was efficiently recovered from the resolution process and pure enough for recycling use. Chiral acid (S)-7 was converted to the corresponding methyl ester (S)-14, which was reduced with NaBH4−CaCl2 to give alcohol intermediate (S)-4. Subsequent mesylation, amination, and salt formation with fumaric acid afforded CP-060S as pure enantiomer (99.8% ee) without any column chromatography.