Study On The Synthesis Of Bosentan

Bosentan was developed by the Swiss company Actelion.And it was approved by the FDA in 2001 for the treatment of patients with III and IV primary pulmonary hypertension or scleroderma caused by pulmonary hypertension.In this paper,based on the systematic analysis of the existing literature,the synthetic route to bosentan was designed and explored.2-Cyanopyrimidine was used as the starting material,it was condensed with sodium methoxide/ammonium chloride to get 2-amidinopyrimidine hydrochloride 2.Diethyl malonate was bromonated with NBS/PTS to yield bromo-diethyl malonate 4,then,it condensed with 2-methoxy phenol to produce methoxy(2-methoxyphenoxy)malonate 5.Compound 2 was reacted with compound 5 to form pyrimidine-4,6-dione 6,followed by cholirazation with POCl3 to get bis-chloropyrimidine derivative 7.Tert-butylbenzene was sulfonated by chlorosulfonic acid and ammonolysis to achieve tert-butylbenzenesulfonamide 10.Condensation reaction of dichloropyrimidine derivative 7 with sulfonamide 10 to get compound 11,which was reacted with ethylene glycol in the presence of t-BuOK to furnish the desired product Bosentan 12.The process has the advantages of inexpensive raw materials,mild reaction conditions,less by-products,high purity and high yield and easy-to-large-scale industrialized production.The structures of the target compounds were confirmed by 1H NMR,13C NMR and mass spectrometry.