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 thyl-7-n-propyl-8-[[2'-(1H-tetraz ol-5-yl)biphenyl- 4-yl]methyl]-[1,2,4]triazolo[1,5-c]pyrimidine (UP 26 9-6, Ripisartan) is described. UP 269-6 is a non-peptide angiotensin I I antagonist currently in phase II clinical trials for the treatment o f hypertension and chronic heart failure. Its development needed a sui table process for industrial production. The laboratory scale synthesi s was optimized and particularly two key steps: 4-hydrazinopyrimidine formation without isolation of the 4-chloro intermediate acid its cycl ization into triazolo[1,5-c]pyrimidine derivative without isolation of the triazolo[4,3-c]pyrimidine isomer using urea in N-methylpyrrolidon e at 160 degrees C. This cyclization process affords a new and efficie nt way to prepare directly 2-hydroxytriazolo[1 5-c]pyrimidine without isolation of the corresponding triazolo[4,3-c] pyrimidine.