Synthesis Of Ezetimibe

Ezetimibe, is a cholesterol-lowering drug, which has developed from Merck andSchering-Plough Corporation. The trade name is EZETROL. Ezetimibe is a novel lipid-lowe-ring drug. There are no domestic manufacturers. The drug’s mechanism of action is unique. Ithas little effect compared with other lipid-lowering drugs, The drug is not only used alone,but also can be combined with other lowering blood lipid medicines. It has good marketprospects.The synthesis of Ezetimibe is very difficult due to it has three chiral carbon atoms andeight isomers. There are four main routes on the synthesis of Ezetimibe At home and abroad,these synthetic routes are mostly with disadvantages of long synthetic steps, harsh reactionconditions, low yield, high cost. In order to simplify the line, increase the yield, reduce thecost, Ezetimibe was synthesized by the (E) -5-(4-fluorophenyl)pent-4-enoic acid instead ofEthyl 4-bromobutyrateas the raw material in the third route,obtained (Z) -5-(4-fluorophenyl)pent-4-enoic acid by the Wittig reaction, then via Chlorization, Amidation, Condensationreaction, cyclization，Wacker-Tsuji oxidation, Corey-Bakshi-Shibata reduction, catalytichydrogenation. This method is more stable intermediates, easily separated, to avoid thecolumn chromatography. Optimized overall yield from 18.8% to 23.5%The intermediates ofEzetimibe are more stable and easily separated and avoiding from the column chromatograph-y, the optimized yield of from22.5% to 26.3%. We use chiral HPLC to analysis the purity anddevelop the single crystal of the key intermediate and its isomer after CBS reduction, and it isdone to confirm the structure by X-ray single crystal diffraction.The purity is 99.6% of the final product (Ezetimibe) and conform to API requirements,by IR, NMR, mass spectrometry, single crystal diffraction to determine its structure.