Preparation And Process Development Of (2R)-2-(6-((4-fluorophenyl)(4-methylpiperidin-1-yl)methyl)-4'-(Trifluoromethyl)biphenyl-3-yl)Propanoic Acid

(2R)-2-(6-((4-fluorophenyl)(4-methylpiperidin-1-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)propanoic acid is a key intermediate of benzhydryl modification analogs as nociceptin receptor ligands.Based on the chemical structure of the target compound, we utilized the disconnection method via retrosynthetic analysis to design several synthetic routes. In this dissertation, a possible route was focused on via total seven steps as follows:i) Using 2-(3-hydroxyphenyl)acetate as starting material, the key intermediate of 2-(6-((4-fluorophenyl)(4-methylpiperidin-1-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl) acetate was obtained via four steps (esterification, Mannich reaction, subtitution and coulpling reaction); iii) After condensation, hydrolysis and asymmetric hydrogenation, the target compound (2R)-2-(6-((4-fluorophenyl)(4-methylpiperidin-1-yl)methyl)-4'-(trifluoromethyl) biphenyl-3-yl)propanoic acid was obtained with a overall yield of 25.9%. As demonstrated, using Ru(OAc)2(R-H8-BINAP) as asymemetric hydrogenation catalyst, the resulting eneantiomer exceed (ee%) can reach 98%, much higer thann other catalysts。...