The Synthesis Of Rosuvastatin And Atorvastatin Side Chain

Cardiovascular disease is a serious threat to human health(especially the eldrly)and is the most common and one of the highest fatality rate of the disease.While syslipidemia,especially abnormally elevated serum total cholesterol(TC)is an important cause of cardiovascular disease.Considering that about 70% of TC is endogenous,inhibiting cholesterol biosynthesis selectively to regulate blood levels has become a viable strategy which can precaution and treat related cardiovascular disease.Lipid-lowering drugs namely the statins,especially rosuvastatin and atrovastatin have becom the leader among it’s market because of their safety and effectiveness.In recent years,under the lead of the market,the synthesis of lower cost and higher putity rosuvastatin and atorvastatin have been the development trendcy of the Lipid-lowering drug market.This paper mainly talk about he synthetic route which is taken(S)-4-chloro-3-hydroxybutyronitrile and tert-butyl bromoacetate as the starting materials,and then through optimizing the Blaise reaction、choosing appropriate reducing agent acted on α-hydroxyl-β-keto ester and chemical resolution condition to achieve the target.Firstly,the starting material(S)-4-chloro-3-hydroxybutyronitrile 1 was treated with protective groups to avoid the corresponding side reactions.The difference between 1 against(S)-4-chloro-3-siloxybutyronitrile 2 acted as the starting material of yield is ignorable,so the protection of hydroxyl is a must to gain a higher yield.Secondly,we investigated the effects of cuprous bromide and iodine separately through the Blaise reaction,a lengthening of carbon chain reaction.It’s turn out that both of them improve the yield in a large scale.Thirdly,considering cuprous bromide and iodine catalyze the different process of the blaise reaction(namely,iodine catalyze the reaction between tert-butyl bromoacetate and zinc to synthesis organozinc reagents,while cuprous bromide catalyze the reaction between organozinc reagent between 2),we tried to applied both of them into the Blaise reaction.The outcome is surprised as the yield was improved to 97.0% compared to 72.1% without any catalysis.Thus inspiring result not only promoted the application of Blaise reaction greatly but also laid foundations for the other similar reactions.The product of Blaise reaction is β-hydroxy keto ester.β-hydroxy keto ester was transformed to dihydroxy ester with KBH4 as the reductive reagent,and then the ortho-dihydroxy of reductive product was protected with DMP,hydrolyze 、 replacement and recrystallization from n-hexane to gain the high purity target product namely rosuvastatin side chain.The reaction between compound 7 of rosuvastatin side chin intermediate and sodium cyanide can introduce the cyano group,which is an important intermediate of atorvastatin side chain.