Study On The Synthesis And Technology Of The Core Of Rosuvastatin Calcium

Rosuvastatin calcium,displays inhibiting activity for HMG-CoA reductase,a major rate-limiting enzyme in cholesterol biosynthesis.And it has been shown to induce the expression of the low-density lipoprotein(LDL)receptor which mediates the clearance of LDL cholesterol from plasma.Compared to other statins,Rosuvastatin is more efficient and exhibits fewer side effects.The core of Rosuvastatin,4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl methanol,which is the important intermediate of the synthesis of Rosuvastatin,is systematically stuied.A novel and efficient five-step synthetic route,including a Biginelli reaction(87% yield),dehydrogenation(96% yield),chlorination(94% yield),sulfonamidation(97% yield)and reduction(84% yield),for the core of Rosuvastatin was established.In our research,all steps were systematically studied.Tert-butylhydroperoxide(TBHP)aqueous solution was applied in the dehydrogenation instead of nitric acid.N,N-dimethylaniline was employed as a catalyst to accelerate the chlorination proceeding smoothly and its catalytic mechanism is discussed.In the sulfonamidation,the conversion of compound 5 was obviously improved by use of NaH and acetonitrile.In addition,two sulfonamidation side products 6 and 7 were detected and isolated.Thus,under the optimized reaction conditions,the target product was obtained in 64% total yield,much higher than the reported yield(36%).