Study On The Synthesis Of Rosuvastatin Intermediate

Rosuvastatin which Chemical name is Bis(3R,5S,6E)-[7-[4-(4-:fluoro-phenyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid]monocalcium salt is HMG-CoA reductase inhibitor developed by Shionogi Seiyku Kabushiki Kaisha,can treat the disorder of high blood-cholesterol,it’s one of the most strongest effect of the cholesterol-lowering drugs.Then Shionogi Seiyku Kabushiki Kaisha transfers this drug to Astra Zeneca UK Ltd.According to the patents,there were two routes followed by reaction of Wittig consendation to synthesis Rosuvastatin,one route was multisubstituted pyrimidine formaldehyde react with phosphonium salt which contains chiral side chain;the other route was chiral side chain react with phosphonium salt contains multisubstituted pyrimidine parent nucleus.Thus the parent nucleus of Rosuvastatin was one of the most important intermediates.According to the previous reports,there were many patents describe the synthesis routes of Rosuvastatin’s parent nucleus(multisubstituted pyrimidine derivative).4-fluoro benzaldehyde and isobutyryl acetate were joint starting material in several synthetic processes,difference in these processes were the other starting materials,some processes used S-Methyl-iso-thiourea sulfate,some used Urea,and some used Thiourea.But all the synthesize processes in these patents used highly toxic and high-polluting chemical reagents.These reagents will easily endanger the environment and human health.Thus,it’s necessary for improving the present processes.This paper used 4-fluoro benzaldehyde and isobutyryl acetate as starting materials,eight steps synthesis the Rosuvastatin’s mother nucleus according to the synthetic process which reported by patent US5260440.This paper highlighted oxidative aromatization of multi-substituted dihydro-pyrimidine and selective oxidation of multi-substituted pyrimidine methanol.Toxic and harmful oxidants were replaced by molecular oxygen in oxidative aromatization and selective oxidation,DDQ/TBN for conversion of multi-substituted dihydro-pyrimidine via aerobic aromatization and TEMPO/TBN for conversion of multi-substituted pyrimidine methanol via aerobic oxidation have been developed.This paper also optimized the remaining steps in the synthetic process.