New process for the synthesis of UP 269‐6 , a 1,2,4‐triazolo[1,5‐ c ]pyrimidine derivative as a potent orally active angiotensin ii antagonist

A new synthetic route to prepare the 2‐hydroxy‐5‐methyl‐7‐ n ‐propyl‐8‐[[2′‐(1 H ‐tetrazol‐5‐yl)biphenyl‐4‐yl]methyl]‐[1,2,4]triazolo[1,5‐ c ]pyrimidine ( UP 269‐6 , Ripisartan) is described. UP 269‐6 is a non‐peptide angiotensin II antagonist currently in phase II clinical trials for the treatment of hypertension and chronic heart failure. Its development needed a suitable process for industrial production. The laboratory scale synthesis was optimized and particularly two key steps: 4‐hydrazinopyrimidine formation without isolation of the 4‐chloro intermediate and its cyclization into triazolo[1,5‐ c ]pyrimidine derivative without isolation of the triazolo[4,3‐ c ]pyrimidine isomer using urea in N ‐methylpyrrolidone at 160°C. This cyclization process affords a new and efficient way to prepare directly 2‐hydroxytriazolo[1,5‐ c ]pyrimidine without isolation of the corresponding triazolo[43‐ c ]pyrimidine.