Studies On The Synthetic Process Of Rosuvastation Calcium

Rosuvastatin Calcium,chemical name(+)-(3R,5S)-7-[4-(4-FluoropHenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid calcium salt,is a member of the drug class of statins to treat high cholesterol.This drug is a competitive inhibitor of the enzyme HMG-CoA reductase,which can significantly lower cholesterol by lowering the biosynthesis of cholesterol with fewer side effects.Renowned as "the super drug of statin",and the research on synthetic process get more and more attention.We selected(S)-4-Chloro-3-hydroxybutyronitrile as the raw material,and through silane protection,ring expanding,catalytic reduction by specific enzymes and acetylation to prepare the intermediate tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyI-1,3-dioxan-4-yl]acetate,which was reacted with nucleus by the WITTIG condensation reaction in the condition of strong base,then followed acid hydrolysis,alkaline hydrolysis,formed Ammonium salt to get solid,converted to calcium salt at last to afford Rosuvastatin Calcium.Moreover,(3R,5S)-tert-butyl-6-chloro-3,5-dihydroxyhexanoate is a key intermediate for the synthesis of dihydroxyl hexylic acid which is pHarmacodynamic group containing two chirals,For this reason,we developed novel enzyme catalysis process with high stereo selectivity,Avoided using dangerous reagents such as borane,borohydride,butyl lithium,etc.The optimum catalytic conditions of enzyme were studied,and the yield and selectivity improved,which were up to 5%and 4%respectively.In order to improve the ratio of anti and cis,we confirmed the condition of WITTIG comdensation reaction to choose DMSO as solvent and CsCO3 as base,which was up to 6:1.What's more we developed crystallization process,Though the screening of crytalline solvents and temperatures,applying isopropanol and acetone as preferred mixed insolvents,crystallization under the temperature of-5?0?,the method with effective removal of isomer impurity,and improved the product quality with total impurities<0.3%and single impurity<0.05%.After the optimization of the whole process,the total yield is 55%(48%reported in literture).The structure of Rosuvastatin Calcium had been confirmed by MS,1H-NMR and 13C-NMR.