Synthesis And Study On Ezetimibe

Ezetimibe was explored successfully by Schering-Plough Research Institute in 1999 and came into market in 2003 as a new drug to resist the assimilation of cholesterol.It controls the assimilation of the cholesterol which comes from outside of the intestine to reduce the blood ester. The discovery of ezetimibe is a breakthrough of the study of the new drug to resist the assimilation of cholesterol which gets the attention of pharmacy aboard.There are three chiral centers in ezetimibe which requires high preparing technology and complicated synthetic technics including the asymmetric synthesis which is more difficult. The product is still under patent protection period and there is no domestic production at present. In this paper, the last three parts of this technics have been completed. The main research work is shown below:1、The study of hydroxyl protection with (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxy-1-oxo-pentyl]-4-phenyl-oxazolidine-2-one (intermediate 6), (E)-4-(4-fluorophenyl imino-methyl) phenol (intermediate 7)Trimethylsilyl was selected as a protective agent, and diisopropylethylamine as base to study hydroxyl protection of intermediates 6 and 7,and the optimum conditions of protection was determined after a series of experiments. The structures of intermediates were characterized by IR,1HNMR and MS.2、The study of Addition Reactions with intermediates 6 and 7In order to save funds, a low-cost model was chosen to study the addition reaction at first and then the intermediates 6 and 7 were used to synthesize intermediate 8 according to the findings of model compounds, for wheat, and process optimization were taken at last.(1)The addition reaction, cyclization reaction were studied with N, N-dimethyl-acetamide and benzylmethylaniline which were selected as a models.The reaction that uses benzaldehyde and aniline to synthesize benzylmethylaniline was studied and the process was optimized.The addition reaction with N, N-dimethylacetamide and benzylmethylaniline under the Catalyst of Lewis acid was studied.And the structure of addition product N,N-dimethyl-3- phenylaminophenylamide was characterized by 1HNMR.The cyclization reaction of N, N-dimethyl-3-phenylaminophenylamide under the presence of N,O-trimethylsilylacetamide and tetrabutylammonium fluoride was studied. Unfortunately, we were failed to get cyclization product, and decided to select a closer mode 3-acetyl-(4S)-phenyl-oxazolidinone to continue our research after extensive testing.(2) The addition reaction, cyclization reaction were studied with 3-acetyl-(4S)-phenyl-oxazolidinone and benzyl methyl aniline which were selected as models.The reaction that uses glacial acetic acid and (4S)-phenyl-oxazolidinone to synthesize 3-acetyl-(4S)-phenyl-oxazolidinone was studied and the process was optimized. The structure of addition product was characterized by MS and 1HNMR.The addition reaction with 3-acetyl-(4S)-phenyl-oxazolidinone and benzylmethylaniline was studied. The best reaction condition was achieved after comprehensive study on the reaction from several aspects. And the structure of addition product was characterized by 1HNMR and MS.The cyclization reaction of addition product which was taken under the presence of N,O-trimethylsilylacetamide and 4-butylammonium fluoride was studied. The best reaction condition was achieved after comprehensive study on the reaction from several aspects. And the structure of cyclization product was characterized by 1HNMR and MS.(3) The addition, cyclization reaction of ezetimibe intermediates were studiedThe addition reaction with ezetimibe intermediates 6 and 7, cyclization reaction with addition product were studied and the processes were optimized referring the synthesis of model compounds.The addition reaction with intermediates 6 and 7 was studied.The cyclization reaction of intermediate 8 which was taken under the presence of N,O-trimethylsilylacetamide(BSA) and tetrabutylammonium fluoride(TBAF) was studied. The best reaction condition was achieved after comprehensive study on the reaction from several aspects.And the structure of product was characterized by IR,1HNMR and MS.3、The synthesis of ezetimibe process conditions was studied by using domestic reagents instead of imported onesSynthesis of ezetimibe is not only a complex process, but also need the reagents quite dry with high purity. In order to protect the research results accurate and reliable, the main raw materials and reagents in the process of research were selected from the Corporation of Sigma-Aldrich or the Company of Alfa Aesar (imported reagents).For the purpose of achieving the industrialization of this process, domestic agents need to be investigated. So a series of experiments were taken with the domestic agents instead of imported ones while keeping other conditions unchanged, and the stability test were also carried out.(1)The addition reaction by using of domestic Lewis acidⅢas catalyst was studied.(2)The cyclization reaction by using of domestic BSA was studied.(3)The cyclization reaction by using of domestic TBAF was studied.