New Method For Synthesis Of Simvastatin

Simvastatin is a cholesterol lowering agent that is partially synthesized from lovastatin. Simvastatin is an inactive lactonization precursor parmaceutical which operated by active metabolites or its derivatives via liver hydrolyzation. Simvastatin can be used in curing hypeholesterol. Lots of clinical tests show that simvastatin can remarkably decrease incidence and the death rate of coronary heart disease , which is characterized by effective adjusting blood lipid levels with few side effects and good endurance of long term use. Simvastatin has been considered to be one of the most effective LDL lowering drug. This study develop a new technology of producing simvastatin which could reach the international advanced level.Simvastatin(SVT) from Tri-lactone acid (TLA) as the important intermediate was synthesized by a ring-expanding method. The conditions of the reaction material and the purification were investigated by the single-factor experiments with fine yield , simple reaction and low cost of simvastatin.(1) The conditions of DMP protect reactionThe optimized synthesis conditions of P-TLA are follows: TLA 13.6g, DMP 20ml, PTS 0. 5g, toluene 200ml, the reaction temperature at 25-30℃, the resuting mixture is agitated under a nitrogen atmosphere. The yield remains relatively high, about 95%,98%.The optimized synthesis conditions of P-SVT1 are follows: the purification P-TLA, pyridine 136ml, DMBC 20ml, DMAP 0. 4g, the temperature at 100-105℃, the mixture was stirred for 6 h under a nitrogen atmosphere, then the temperature at 15-20℃, it is added to water 50ml, the yield was about 90%, 95% after purification.The optimized synthesis conditions of SVT are follows: the P-SVT1 after purification, acetonitrile 200ml, 1.0mol/L HCl 20ml, the reaction temperature between 25-30℃, the mixture was agitated under a nitrogen atmosphere, the route comprise of synthesis of simvastatin acid and its further lactonization to simvastatin.(2) The conditions of silylating agent protection...