Study On Synthesis Of Sacubitril

Heart failure is a debilitating lethal disease,which makes the heart can't pump enough blood supply to the whole body,and then causes dyspnea,fatigue and other symptoms.Heart failure has significant impact on the patients' quality of life.More than $100 billion is cost because of heart failure every year,with 60-70%useing for hospitalization.Entresto is a heart failure drug,which is composed by Sacubitril and Valsartan.Entresto is the first angiotensin receptor-enkephalin enzyme double inhibitors.Sacubitril is a kind of enkephalin enzyme inhibitor,which can prevent the degradation of diuresis sodium peptide and can benefit the cardioascular and renal function in patients with heart failure.Valsartan is a kind of target angiotensin receptor,which has high selectivity and special direct effect.Through literature research,we found that the reported synthesis methods of Sacubitril had some disadvantages including rare starting meterials,many reaction steps and low reaction yield.In this paper,we synthesized Sacubitril with cheap chiral amino acids(D-tyrosine)as the starting material,through reduction,oxidation,Wittig reaction,hydrogenation reduction,protection and deprotection.The whole synthesis route included nine steps with mild reaction condition and reduction cost.Furthermore,we synthesized Sacubitril with L-menthol as a chiral center,through esterification,salification,eliminate,additive reaction,Wittig reaction,hydrogenation reduction,protection and deprotection.The whole synthesis route included eleven steps with good chiral separation effect.At last,we optimized the above two synthesis routes from ten steps down to seven steps with one-pot strategy,which improved the reaction yield greatly and reduced the cost.