Studies On The Synthesis Of LCZ696

Chronic heart failure(CHF)is the terminal stage of various cardiovascular diseases and the main cause of death.Heart failure can lead to neuroendocrine compensatory changes,including the excessive activation of sympathetic nervous system(SNS)and rennin-angiotensin-aldosterone system(RAAS).The conventional drug treatment for CHF gives priority to "strengthening heart","diuresis",and"dilating blood vessels".Though the conventional therapy can effectively improve symptoms in patients with heart failure.it can result in serious cardiac decompensation.With the understanding of the pathophysiology,neuroendocrine blocking and ventricular remodeling inhibition gradually replace the traditional treatment.Angiotensin converting enzyme inhibitors(ACEI),?-receptor blockers,and aldosterone receptor antagonists have become the "golden triangle" for the treatment of CHF,and are widely used in clinical.Hovwever,the current drugs can only block the activation of SNS or RAAS,and the long-term treatment can easily cause low blood pressure,renal insufficiency,or the worsening of heart failure.In recent years,with the application of several new drugs(LCZ696.Ivabradine and traditional Chinese medicine Qiliqiangxin capsule)with new therapeutic mechanism,major breakthroughs have been made in drug treatment for heart failure.LCZ696 is a new type of single molecule drug developed by Novartis,used in the treatment of lower left entricular ejection fraction of CHF.In clinical research,cardiovascular death risk is decreased by 20%.and the lower risk of hospitalization is 21%.The U.S.food and drug administration(FDA),the European medicines agency(EMEA)approved LCZ696 in July and November 2015,respectively.LCZ696 is composed of valsartan and sacubitril(AHU377),the precursor drug of enkephalin inhibitor,by a molar ratio of 1:1,with multiple functions in a unique way.LCZ696 can not only inhibit harmful effects caused by the RAAS activation,but also enhance the neuroendocrine system(natriuretic peptide system)to protect the heart.Although there are some reports regarding the synthesis of LCZ696,many problems still exist,such as complicated reaction operations,unsuitable for large scale production,low yield,etc.In this study,a new synthetic route is designed to solve these problems,tert-butyl((27R)-1-(biphenyl-4-yl)-3-hydroxypropan-2-yl)carbamate is used as the starting material,and primary alcohol is oxidized to generate aldehyde using Anelli,and then olefine acid(intermediate 1)is prepared followed by Wittig and alkaline hydrolysis.Intermediate 1 is hydrogenated using a chiral ruthenium catalyst to afford intermediate 2.Esterification of intermediate 2 with ethanol and concomitant deprotection of the Boc group is induced by treatment with thionyl chloride in ethanol.The amino ester intermediate 3 is obtained as the hydrochloride salt.Intermediate 3 is converted to sacubitril upon treatment with succinic anhydride and triethylamine in isopropyl acetate.Addition of aqueous sodium hydroxide solution leads to deprotonation of the free acid and affords the water-soluble sodium salt of sacubitril.Precipitation of the calcium salt(intermediate 4)is then achieved through mixing of calcium chloride and an aqueous solution of sodium salt of sacubitril.Intermediate 4 is mixed with isopropyl acetate,and the acid sacubitril is liberated by acidification with aqueous HCl.Following an aqueous work-up,the solution of sacubitril in isopropyl acetate is subjected to a solvent exchange to isopropanol.Valsartan and acetone are added,and the resulting mixture is treated with aqueous sodium hydroxide solution.LCZ696 is isolated by filtration and washed with acetone.The qualified LCZ696 is prepared after drying.In the preparation of LCZ696,some reaction and workup conditions are optimized.In the Anelli oxidation,the reaction temperature and the oxidant ratio are determined.In the Wittig reaction,solubility difference is utilized to separate the product from the resulting Ph3PO by using a mixture of hexane and ethyl acetate in a ratio of 1:6 to 1:7,avoiding the column chromatographic purification.In the conversion of the acid into ethyl ester to prepare intermediate 3,the reaction conditions are optimized.Calcium salt of sacubitril(intermediate 4)is prepared in favor of the storage.In the synthesis of LCZ696,acetone/isopropanol is used as crystallization solvent to give the product in high yield and good purity.With these improvements,the synthetic process of LCZ696 is established.In addition,the main related impurities are also analyzed and prepared.