Synthetic Process Of Cardiotonic Agent Sacubitril/Valsartan Sodium

Sacubitril/valsartan sodium,sold under the brand name Entresto,is a combination drug for use in heart failure developed by Novartis,and it consists of the angiotension II inhibitor valsartan and the neprilysin inhibitor sacubitril.Entresto is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart.failure and reduced ejection fraction.Sacubitril/valsartan sodium is the first widely used chronic heart failure drug in the past 20 years.It was approved by FDA on July 7,2015.Because heart failure is one of the most important causes of death in adults and there are almost no similar products competing with Entresto in market,so this product has a good sales prospect.The present study integrated literatures and developed a novel process for preparing a key intermediate of sacubitril to overcome drawbacks of disclosed process in existing literature.On the basis of this,we designed a novel,low cost,environment-friendly and industrially advantageous process for the preparation of sacubitril/valsartan sodium.The process used D(+)-phenylalanine as starting material and through iodonation,reduction,N-Boc protection and Suzuki coupling reaction to provide the key intermediate of tert-butyl(R)-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate,Followed a serial of reactions by TEMPO catalyzed oxidation,condensation,hydrolysis and asymmetric hydrogenated reduction gave(2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl pentanoic acid.Then,the followed reactions of deprotection,esterification,condensation with succinic anhydride and salify process provided Sacubitril Hemicalcium in good yield.Finally,the target product of Sacubitril/Valsartan sodium was obtained by converting sacubitril hemicalcium to its free acid and cocrystallization with valsartan in the presence of sodium hydroxide.The total yield of the synthesis of Sacubitril/Valsartan sodium is 25.6%?...