Synthesis And Process Optimization Of Ezetimibe As Hypolipidemic Drug

Ezetimibe is the first new oral lipid-lowering drug approved by FDA for selective absorption and inhibition of cholesterol,which has certain advantages over other current lipid-lowering drugs.It is mainly combined with specific transporters on the wall of the small intestine to inhibit the absorption of cholesterol and phytosterols in the small intestine,reduce the transfer of cholesterol from the intestine to the liver,reduce storage and eliminate cholesterol in the plasma as much as possible,so as to reduce the level of plasma cholesterol.As a first-line drug,it is widely used in clinical treatment.Whether it is used alone or in combination（such as statins）,it is the best choice to reduce blood lipid.The drug has high safety,strong stability and obvious effect.It has good application value in the drug market for the treatment of hyperlipidemia.In this thesis,the small-scale process optimization and pilot production of ezetimibe have been carried out,and the possible impurities in the process route have been directionally synthesized.The research contents are as follows:（1）In the second chapter,4-（4-fluorobenzoyl）butyric acid（2）was synthesized from glutaric anhydride and fluorobenzene by Friedel-crafts acylation,and hydroxyl-lamine condensation with chiral molecules to form（4S）-3-[5-（4-fluorophenyl）-5-oxopentanoyl]-4-phenyl-1,3-oxazolidin-2-one（3）,and（4S）-3-[（5S）-5-（4-fluoropheny-l）-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one（4）was synthesized by chiral catalysis and asymmetric carbonyl reduction;Using 4-hydroxybenzaldehyde and 4-fluoroaniline as raw materials,aldehyde amine condensation was carried out to produce 4-{[（4-fluorophenyl）imino]methyl}phenol（5）,and Mannich-like addition with compound 4 to form key intermediate（S）-3-{（2R,5S）-5-（4-fluorophenyl）-2-（（S）-[（4-fluorophenyl）amino]{4-[（trimethylsilyl）oxy]phenyl}methyl）-5-[（trimethylsilyl）oxy]-pentaneyl}-4-phenyloxazolidin-2-one（6）,and ezetimibe（1）is obtained through cyclization;The process of each step was optimized and improved.The yield of 2 was 85.0%（molar）,and the purity was 99.10%by HPLC;The yield of 3 was 95.0%（molar）,and the purity of 98.05%（HPLC）;The yield of 4was 96.0%（molar）,and the purity of 96.66%（HPLC）;The yield of 5 was 96.0%（molar）,and the purity of 99.42%（HPLC）;The yield of 6 was 63.2%（molar）,and the purity of crude product was97.28%（HPLC）,specific rotation[α]_D²⁰=-34.8°.By recrystallization,the purity of fine pruduct was 98.96%（HPLC）;The yield of 1 was 94.0%（molar）and the purity of crude product was 99.08%（HPLC）,specific rotation[α]_D²⁰=-25.6°,the refining yield was 90.7%,and the purity of fine product was 99.87%（HPLC）;The total yield was 40.1%.（2）In the third chapter,the synthesis of 5,6 and 1 and the purification of the product were amplified（starting from the feeding amount of 1.8 kg）.The molar yields were 94.0%,55.6%,91.5%and 87.5%respectively.The total yield of the four-step pilot test was 41.8%and the purity of finished product was 99.74%（HPLC）.（3）In the fourth chapter,18 impurities that might appear in the process route were directionally synthesized.Impurities M and I could be detected in the pilot product ezetimibe,and their relative peak areas were less than 0.10%.The product detected by HPLC from the optical isomer is 99.88%,and the detectable impurity D is 0.04%.The intermediates,products and impurities studied in this thesis were characterized and tested by HPLC,MS,FTIR,¹H NMR and polarimeter.The thesis has 52 figures,43 tables and 51 references.