Synthesis And Process Optimization Of Sacubitril

Sacubitril is a type of neprilysin inhibitors,It mix with angiotensin? inhibitor Valsartan then gain the anti-heart failure drug Entresto that is the new type of anti-heart failure drug.Entresto has a very good anti heart failure effect,can significantly reduce the risk of death and hospitalization risk of heart failure,also has the advantages of small toxic side effect,high efficacy at low dosage and other advantages.It has been proved that Entresto has become one of the most important drugs for the new generation of dual inhibitor of angiotensin ? and encephalin.Sactubitril is the important ingredients of Entresto,There has many way to synthesis Sacubitril,but most of them have many drawbacks,such as using expensive material as the starting material,synthesis is complexity,and producing more waste in the post-processing.So synthetic route to Sacubitril is simple,cheap,green,can be industrialized has a very important significance.This paper summarize the papers at home and abroad about Sacubitril,In experiment,We repeated the systhesis route with 4-Bromobipenyl as starting material,Sacubitril was obtained via Grignard reaction,Mitsunobu reaction,hydrolysis,oxidation,Wittig reaction,de-protect group reaction,aminolysis.Base on the demerit and merits of existing synthesis routle,We designed a new synthesis routle with D-phenylalanine as starting material.Sacubitril was obtained via replace by iodine reaction,carboxyl and amino protective reaction,reduction reaction,Parikh-Doering oxidation,Wittig reaction,de-protect group reaction,amiolysis.The total yield of the route is 28.1%.The operation is simple,the total yield is high,the raw material cost is low,and the utility model has high industrial application value.In the new method for the synthesis of Sacubitril,the key step is the Suzuki reaction,the reduction of the ester compound to the aldehyde group and the asymmetric hydrogenation of the three steps.The Suzuki reaction is the key to select the appropriate catalyst,reduction of ester compounds is key to select the appropriate reduction method,asymmetric hydrogenation is the key step of the route,choose a suitable catalyst stereoselectivity is very difficult.In this paper,the synthetic route of Sacubitril was comprehensively evaluated,and a new route for the synthesis of Sacubitril was designed.The reaction products in the route were characterized by NMR and MS.