Synthesis Of Fasidotril

Hypertension is a cardiovascular disease that harms the health of people severely. It can easily develop complications such as cerebral apoplexy, coronary heart disease, myocardial infarction, heart failure and renal failure.Drugs in common use include: diuretics, beta-blockers, angiotensin converting enzyme inhibitors(ACEI), angiotensin receptor blockers(ARB), calcium channel blockers (CCBs) and aldosterone antagonists. Fasidotril, L-Alanine, N-[(2S)-3-(acetylthio)-2-(1,3-benzodioxol-5-ylmethyl)-1-oxopropyl]-, phenylmethyl ester, is the peroral prodrug of Alatrioprilat. It is a dual ACE/NEP inhibitor. Fasidotril inhibits potency towards ACE and NEP, hence resulting in protection of natriuretic peptides and bradykinin to prevent angiotensinâ…¡formation. At the same time, it can also help to inhibit myocardial hypertrophy, improve the heart and renal function. It is the representation drug of hypertension and heart failure in future. It was created by Bioprojet Company of France, delegated to Lilly Company of America in 2001. Now it is underâ…¡~â…¢clinical stage.The synthesis routes of Fasidotril were researched in this thesis. Catechol was selected as the raw material, through cyclization, chloromethylation, alkylation, hydrolysis, Mannich-elimination reaction, addition, anhydration and condensation, then the target product Fasidotril was prepared in total yield 17.5%. During the synthesis of Fasidotril, the key intermediates, piperonyl chloride and 2-[(3, 4-methylenedioxy phenyl)methyl]propenoic acid were synthesized in higher yield, shorter period and higher economic returns because of the improvement that made to the routes. Efforts also made to improve the synthesis from 2-[(3, 4-methylenedioxy phenyl)methyl]propenoic acid to Fasidotril. The new method includes chloridation, condensation and addition three steps. That Simplified the purification of target product with lower cost. It was proved right by the data of 1H NMR spectra and melting point.The structures of the key intermediate and the target product were confirmed by 1H NMR spectra.