Study In The Preparation Process Of Novel Cholesterol Absorption Inhibitor-Ezetimibe

Ezetimibe, as a novel lipid-lowing drug approved by FDA in 2002, was prescribed for the treatment of hypercholesterolemia. The agent can bind to the cholesterol transport protein NPC1L1 and block the absorption of cholesterol in the small intestine, thereby reducing cholesterol levels in plasma and liver. Ezetimibe is the first drug that selectively inhibits the absorption of cholesterol with excellent safety and tolerability.Based on the reported synthetic routes in literatures, we found a novel way to get Ezetimibe. The fluorobenzene was used as starting material, with a sequence of Friedel-Crafts acylation, amidation, chiral reduction, hydroxyl-moiety protection, Mannich-mimic condensation, cyclization and catalytic hydrogenation to yield the final product in 10 steps. The structure of Ezetimibe was identified by 1H-NMR,13C-NMR, MS and melting point. The chiral purity of Ezetimibe was confirmed by positive HPLC and specific optical rotation. The overall yield of this route is about 45%, higher than that reported in the literature. This synthetic route features widely available starting materials, easy operation and mild reaction condition. Therefore, it’s suitable for industry production.