Study On Synthesis Of New Cholesterol Absorption Inhibitor Ezetimibe And Its Intermediates

Ezetimibe is a new selective cholesterol absorption inhibitor which was commonly researched and developed by Merck and Schering-Plough Pharmaceuticals,Inc.. Based on the literatures, this paper selected fluorobenzene and glutaric anhydride as the starting materials, after Friedel-Crafts reaction, chiral auxiliary introduction, chiral reduction, hydroxyl-group protection, imine condensation and cyclization, the final product ezetimibe was getting. This route is simple, raw materials easy getting, mild condition and good yields for industry producing.In the first step, flourobenzene and glutaric anhydride was catalyzed by anhydrous aluminum chloride though Friedel-Crafts acylation to generate fluorobenzoyl butyric acid. The optimal condition was got after several attempts.In the second step, fluorobenzoyl butyric acid reacted with pivaloyl chloride to get the mixed anhydride, then with the chiral auxiliary (4S)-4-phenyl-2-oxazolidinone to generate the intermediate. After the attempt of a variety of the solvents and the ratios, the best reaction condition was generated.In the third step, p-fluoroaniline and p-hydroxybenzaldehyde used the alcohol as the solvent, to get4-(4-hydroxybenzylidene)fluoroaniline, and then several hydroxyl-protecting groups were used to protect the hydroxyl. After the experiment, the best reaction condition was got.The step four was using methoxyamine hydrochloride as the protecting group to protect the carbonyl to get oxime under the organic base, and the best condition was got after several experiments.The step five was the reaction between the fourth step product and the benzyloxy protected third step product.In this reaction, TiCl4as the main catalyst, Ti(O-i-pr)4as the co-catalyst and the organic base DIPEA these three combined together to get the cyclization product.We concluded the reaction mechanism,and searched the raw materials and catalysts ratio, finally got the optimal condition.The step six is the chiral reduction, the paper used two chiral reducing agents,(-)-DIPC1and (R)-MeCBS and BMS, to reducing the product prepared by step two.With several attempts, and the final resoult was that3eq reducing agent was the best dosage to reducing the product when (-)-DIPC1was used, and0.15eq (R)-MeCBS,2eq BMS was the best ratio to reducing the product. Comparing these two reducing agents,(R)-MeCBS and BMS was more suitable for industry producing.The step seven was the reaction between the product prepared by step three and step six which the hydroxyl was protected by TMSC1under the orangic base DIPEA, then the catalyst TiCl4and Ti(O-i-pr)4were added to condensate to get imine, and the best condition was got after several experiments.In the eighth step, ezetimibe was synthezed after cyclization and deprotection which BSA as silanization agent, TBAF as cyclization catalyst and deprotection agent. After the experiment, the best reaction condition was got.