Study Of Aldol Condensation Of Chan's Diene Promoted By A Ti(â…£)/binol Complex And Synthesis Of Hypocholesterolemic Agent Ci-1011

The first part of this thesis is about the study of Aldol reaction promoted by Ti(IV)/BINOL.1, 3-bis(trimethylsilyloxy)-1-methoxy-1, 3-butadiene, also known as chan's diene , has been used as nucleophilic reagent to formδ-hydroxy-β-ketoesters by reacting with aldehydes. If catalyzed by Ti(IV)/BINOL , the reaction can selectively form different chiral substances. However, the selectivity of some reaction was not high and all of the reactions were performed at -78℃.For many products are used to treat arteriosclerosis and hyperlipidemia, we carefully studied the effect of amount of catalyst and nonchiral additives , temperature, and different aldehydes . Then we found that proper amount of water could improve greatly the yield and the selectivity and all these reactions could be performed at room temperature .we also reduced the amount of catalyst from 8%mol to 2%mol .we think these findings is very helpful for the synthesis of chiral drugs.The second part of this thesis is about the synthesis of CI-1011. CI-1011 is a drug to treat arteriosclerosis and hyperlipidemia, which is inhibitor of acylcoenzyme A:cholesterolacyltransferase(ACAT). By comparing several synthetic routes, we chosen a practical synthetic route which is suitable for large-scale preparation. In this part CI-1011 was obtained with 1,3,5-triisopropylbenzene as the starting material, which was then reacted with glyoxylic acid followed by the reduction to form 2,4,6-triisoproplyphenylacetic acid, a key intermediate. Commercially available 2,6-diisopropylphenol was converted to [(2,6-diisopropylphenyl)-oxy]sulfonyl isocyanate when reacted with chlorosulfonyl isocyanate , the other key intermediate. A process was developed to couple the two intermediates to give the final pharmaceutical priduct. We improved the key steps and improved yield and excellent reagent condition were found to avoid column chromatograph.