The Synthesis And Optimization Of Atorvastatin And Rosuvastatin Side Chain

Hyperlipidemia is an important factor leading to cardiovascular and cerebrovascular diseases.Statins are widely used because of their strong potency and high safety,and two best of them are Rosuvastatin and Atorvastatin.It’s important to develop low cost,high yield side chain synthesis routes of Rosuvastatin and Atorvastatin.We used a cheap raw material-（S）-4-chloro-3-hydroxybutyronitrile to synthesize Rosuvastatin and Atorvastatin side chains at the same time.The total yield of Rosuvastatin side chain was 51%,Atorvastatin side chain was 44%.（S）-4-chloro-3-hydroxybutyronitrile was used to synthetize Rosuvastatin side chain（（4R-cis）-6-acetyl methyl-2,2-dimethyl-1,3-dioxane-4-tertiary butyl acetate）.Weusedtrimethylchlorosilanetoprotectthelivelyhydroxyof（S）-4-chloro-3-hydroxybutyronitrile,then the product was reacted with tert-butyl bromoacetate,catalyzed by CuBr/I₂,which is named Blaise reaction,to getδ-hydroxy-β-ketone ester compound 4.The carbonyl group of 4 was stereoselective reduced to get 1,3-dihydroxyl compound 5.Dihydroxyl protection reaction,chiral split reaction,acetyl substituted reaction were conducted to obtain Rosuvastatin side chain 8.Emphasis of this research was reduction effects of different reductans in stereoselective reduction,results showed that chiral reduction effect of sodium borohydride/diethyl methoxy borane is best,potassium borohydride was followed,zinc borohydride was between potassium borohydride and sodium borohydride,sodium borohydride/ioctyl sulfosuccinate sodium salt was the worst.Total yield of the synthetic route of Rosuvastatin side chain was 51%.Intermediate of Rosuvastatin side chain-1,3-dihydroxyl compound 5 was used to produced Atorvastatin side chain（（4R,6R）-6-（2-aminoethyl）-2,2-dimethyl-1,3-dioxane-4-tertiary butyl acetate）.Cyano group substituted reaction,dihydroxyl protection reaction,chiral split reaction,cyano group reduction were conducted to produce Atorvastatin side chain C-9.Emphasis of this research were NaCN dosage,class and dosage of catalyst,time,temperature in cyanogroup substituted reaction,and yield was improved from 53.21%without catalyst to 64.96%.We also researched the best dosage of 2,2-dimethoxypropane in dihydroxyl protection reaction,and the yield was 80.99%.In chiral split reaction,we studied hydrolysis effect under different conditions,results showed that the best condition was hydrolyzing with 2M dilute hydrochloric acid in hydrolysis 5 h.Total yield of the synthetic route of Atorvastatin side chain reduced by sodium borohydride/diethyl methoxy borane was 44%.